Breast Cancer

In the past decade, breastfeeding rates have increased substantially. Between 2000 and 2015, the proportion of infants who continued to breastfeed at 12 months increased from 16% to 36%. The proportion of infants who had any breastfeeding increased from 71% to 83%.¹ While the infant health benefits of breastfeeding are widely recognized, the maternal health benefits of breastfeeding are many and likely underappreciated.

Infant health benefits of breastfeeding

There are no large-scale, randomized studies of the long-term health benefits of breastfeeding versus formula feeding. The evidence supporting the health benefits of breastfeeding is derived from case-control and cohort studies. Breastfeeding directly benefits newborn and infant nutrition, gastrointestinal function, host defense, and psychological well-being. Compared with formula-fed newborns, breastfed infants have a reduced risk of infectious diseases including otitis media, gastroenteritis, respiratory infections, sudden infant death syndrome, and metabolic disease. These benefits alone strongly support the public health benefit of breastfeeding.² In addition, breastfeeding greatly benefits maternal health.

Maternal health benefits of breastfeeding

Breastfeeding reduces a woman’s risk for type 2 diabetes, hypertension, and coronary artery disease, myocardial infarction, as well as breast, ovarian, and endometrial cancer. There are few exposures that have such a multitude of positive health benefits.

filler 

Type 2 diabetes

In a prospective cohort study of 1,238 women without diabetes in 1985–1986, 182 women developed type 2 diabetes after 30 years of follow-up. Compared with never breastfeeding, breastfeeding for 0 to 6 months, >6 months to <12 months, or ≥12 months reduced the risk of type 2 diabetes by 25%, 48%, and 69% respectively.³ In the prospective Nurses’ Health Study, among parous women, each additional year of breastfeeding decreased the risk of type 2 diabetes by 15% compared with women who did not breastfeed.⁴

Hypertension

In the Women’s Health Initiative (WHI) study of postmenopausal women, a lifetime history of breastfeeding for 12 months or more was associated with a 12% decrease in the risk of hypertension.⁵ For parous women, the prevalence of hypertension among breastfeeding (≥12 months) and never breastfeeding women was estimated to be 38.6% versus 42.1%.⁵ Similar results were observed in the Nurses’ Health Study II.⁶

Myocardial infarction and coronary heart disease

In the prospective Nurses’ Health Study, during 1,350,965 person-years of follow-up, 2,540 women had a myocardial infarction (MI). Women who had breastfed for ≥ 2 years had a 37% decreased risk of MI compared with women who never breastfed. After adjustment for family history, lifestyle factors, and adiposity, the observed reduction in risk was 23%.⁷ In the WHI (observational study plus controlled trial), women with a single live birth who breastfed for 7 to 12 months had a lower risk of cardiovascular disease than women with a single live birth who did not breastfeed (hazard ratio, 0.72; 95% confidence interval, 0.53–97).⁵

Breast cancer

In a systematic review and meta-analysis of 100 publications, breastfeeding >12 months reduced the risk of breast cancer by 26%.⁸ In a systematic review of 47 studies, the relative risk of breast cancer decreased by 4.7% for every 12 months of breastfeeding.⁹ In a systematic review and meta-analysis of 3 studies, ever breastfeeding was associated with a 28% reduced risk for triple-negative (ER-, PR-, HER2-) breast cancer among parous women.¹⁰ Triple-negative breast cancer generally has a poorer prognosis than receptor-positive breast cancers.

Continue to: Ovarian Cancer

In a systematic review and meta-analysis of 40 publications, ever breastfeeding was associated with a 37% reduction in the risk of ovarian cancer.⁸ In a prospective study of 1.1 million women in the United Kingdom, 8,719 developed ovarian cancer. Among parous women, ovarian cancer risk was reduced by 10% for every 12 months of breastfeeding.¹¹

Endometrial cancer

In a meta-analysis of 17 publications, including 8,981 cases and 17,241 controls, ever breastfeeding was associated with an 11% reduction in breast cancer risk.¹² In a meta-analysis of 15 publications with 6,704 cases, breastfeeding was associated with a 26% reduction in endometrial cancer. After controlling for hormone use and body mass index, the reduced risk was in the range of 35%. A linear relationship between breastfeeding and reduced risk of endometrial cancer was observed, with 1 month of breastfeeding being associated with a 1.2% reduction in the risk of endometrial cancer.¹³

Let’s support our patients’ health by encouraging successful breastfeeding

Obstetrician-gynecologists play an important role in helping women make informed decisions about breastfeeding. Most professional organizations, including the American College of Obstetricians and Gynecologists, recommend exclusive breastfeeding for the first 6 months of life, with continued breastfeeding and introduction of complementary food from 6 to 12 months.^14,15 Birth practices that help to increase successful breastfeeding include:

• inform all pregnant women about the newborn and maternal health benefits and management of breastfeeding
• initiate skin-to-skin contact at birth
• encourage the initiation of breastfeeding within 1 hour of birth
• ensure that breastfeeding newborns do not receive any food or drink other than breast milk, unless medically indicated
• encourage breastfeeding women to not use pacifiers or artificial nipples.¹⁵

When women are discharged from the maternity center, providing information about community-based lactation support is helpful in ensuring continuation of successful breastfeeding.¹⁶

Most patients know that exercise and maintaining a healthy weight can reduce the risk of developing many prevalent diseases. However, far fewer patients know that breastfeeding can reduce the risk of developing type 2 diabetes, hypertension, and coronary artery disease, as well as breast, ovarian, and endometrial cancers. Educating our patients about these health benefits may help them to more fully commit to breastfeeding.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In the past decade, breastfeeding rates have increased substantially. Between 2000 and 2015, the proportion of infants who continued to breastfeed at 12 months increased from 16% to 36%. The proportion of infants who had any breastfeeding increased from 71% to 83%.¹ While the infant health benefits of breastfeeding are widely recognized, the maternal health benefits of breastfeeding are many and likely underappreciated.

Infant health benefits of breastfeeding

There are no large-scale, randomized studies of the long-term health benefits of breastfeeding versus formula feeding. The evidence supporting the health benefits of breastfeeding is derived from case-control and cohort studies. Breastfeeding directly benefits newborn and infant nutrition, gastrointestinal function, host defense, and psychological well-being. Compared with formula-fed newborns, breastfed infants have a reduced risk of infectious diseases including otitis media, gastroenteritis, respiratory infections, sudden infant death syndrome, and metabolic disease. These benefits alone strongly support the public health benefit of breastfeeding.² In addition, breastfeeding greatly benefits maternal health.

Maternal health benefits of breastfeeding

Breastfeeding reduces a woman’s risk for type 2 diabetes, hypertension, and coronary artery disease, myocardial infarction, as well as breast, ovarian, and endometrial cancer. There are few exposures that have such a multitude of positive health benefits.

filler 

Type 2 diabetes

In a prospective cohort study of 1,238 women without diabetes in 1985–1986, 182 women developed type 2 diabetes after 30 years of follow-up. Compared with never breastfeeding, breastfeeding for 0 to 6 months, >6 months to <12 months, or ≥12 months reduced the risk of type 2 diabetes by 25%, 48%, and 69% respectively.³ In the prospective Nurses’ Health Study, among parous women, each additional year of breastfeeding decreased the risk of type 2 diabetes by 15% compared with women who did not breastfeed.⁴

Hypertension

In the Women’s Health Initiative (WHI) study of postmenopausal women, a lifetime history of breastfeeding for 12 months or more was associated with a 12% decrease in the risk of hypertension.⁵ For parous women, the prevalence of hypertension among breastfeeding (≥12 months) and never breastfeeding women was estimated to be 38.6% versus 42.1%.⁵ Similar results were observed in the Nurses’ Health Study II.⁶

Myocardial infarction and coronary heart disease

In the prospective Nurses’ Health Study, during 1,350,965 person-years of follow-up, 2,540 women had a myocardial infarction (MI). Women who had breastfed for ≥ 2 years had a 37% decreased risk of MI compared with women who never breastfed. After adjustment for family history, lifestyle factors, and adiposity, the observed reduction in risk was 23%.⁷ In the WHI (observational study plus controlled trial), women with a single live birth who breastfed for 7 to 12 months had a lower risk of cardiovascular disease than women with a single live birth who did not breastfeed (hazard ratio, 0.72; 95% confidence interval, 0.53–97).⁵

Breast cancer

In a systematic review and meta-analysis of 100 publications, breastfeeding >12 months reduced the risk of breast cancer by 26%.⁸ In a systematic review of 47 studies, the relative risk of breast cancer decreased by 4.7% for every 12 months of breastfeeding.⁹ In a systematic review and meta-analysis of 3 studies, ever breastfeeding was associated with a 28% reduced risk for triple-negative (ER-, PR-, HER2-) breast cancer among parous women.¹⁰ Triple-negative breast cancer generally has a poorer prognosis than receptor-positive breast cancers.

Continue to: Ovarian Cancer

In a systematic review and meta-analysis of 40 publications, ever breastfeeding was associated with a 37% reduction in the risk of ovarian cancer.⁸ In a prospective study of 1.1 million women in the United Kingdom, 8,719 developed ovarian cancer. Among parous women, ovarian cancer risk was reduced by 10% for every 12 months of breastfeeding.¹¹

Endometrial cancer

In a meta-analysis of 17 publications, including 8,981 cases and 17,241 controls, ever breastfeeding was associated with an 11% reduction in breast cancer risk.¹² In a meta-analysis of 15 publications with 6,704 cases, breastfeeding was associated with a 26% reduction in endometrial cancer. After controlling for hormone use and body mass index, the reduced risk was in the range of 35%. A linear relationship between breastfeeding and reduced risk of endometrial cancer was observed, with 1 month of breastfeeding being associated with a 1.2% reduction in the risk of endometrial cancer.¹³

Let’s support our patients’ health by encouraging successful breastfeeding

Obstetrician-gynecologists play an important role in helping women make informed decisions about breastfeeding. Most professional organizations, including the American College of Obstetricians and Gynecologists, recommend exclusive breastfeeding for the first 6 months of life, with continued breastfeeding and introduction of complementary food from 6 to 12 months.^14,15 Birth practices that help to increase successful breastfeeding include:

• inform all pregnant women about the newborn and maternal health benefits and management of breastfeeding
• initiate skin-to-skin contact at birth
• encourage the initiation of breastfeeding within 1 hour of birth
• ensure that breastfeeding newborns do not receive any food or drink other than breast milk, unless medically indicated
• encourage breastfeeding women to not use pacifiers or artificial nipples.¹⁵

When women are discharged from the maternity center, providing information about community-based lactation support is helpful in ensuring continuation of successful breastfeeding.¹⁶

Most patients know that exercise and maintaining a healthy weight can reduce the risk of developing many prevalent diseases. However, far fewer patients know that breastfeeding can reduce the risk of developing type 2 diabetes, hypertension, and coronary artery disease, as well as breast, ovarian, and endometrial cancers. Educating our patients about these health benefits may help them to more fully commit to breastfeeding.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In the past decade, breastfeeding rates have increased substantially. Between 2000 and 2015, the proportion of infants who continued to breastfeed at 12 months increased from 16% to 36%. The proportion of infants who had any breastfeeding increased from 71% to 83%.¹ While the infant health benefits of breastfeeding are widely recognized, the maternal health benefits of breastfeeding are many and likely underappreciated.

Infant health benefits of breastfeeding

There are no large-scale, randomized studies of the long-term health benefits of breastfeeding versus formula feeding. The evidence supporting the health benefits of breastfeeding is derived from case-control and cohort studies. Breastfeeding directly benefits newborn and infant nutrition, gastrointestinal function, host defense, and psychological well-being. Compared with formula-fed newborns, breastfed infants have a reduced risk of infectious diseases including otitis media, gastroenteritis, respiratory infections, sudden infant death syndrome, and metabolic disease. These benefits alone strongly support the public health benefit of breastfeeding.² In addition, breastfeeding greatly benefits maternal health.

Maternal health benefits of breastfeeding

Breastfeeding reduces a woman’s risk for type 2 diabetes, hypertension, and coronary artery disease, myocardial infarction, as well as breast, ovarian, and endometrial cancer. There are few exposures that have such a multitude of positive health benefits.

filler 

Type 2 diabetes

In a prospective cohort study of 1,238 women without diabetes in 1985–1986, 182 women developed type 2 diabetes after 30 years of follow-up. Compared with never breastfeeding, breastfeeding for 0 to 6 months, >6 months to <12 months, or ≥12 months reduced the risk of type 2 diabetes by 25%, 48%, and 69% respectively.³ In the prospective Nurses’ Health Study, among parous women, each additional year of breastfeeding decreased the risk of type 2 diabetes by 15% compared with women who did not breastfeed.⁴

Hypertension

In the Women’s Health Initiative (WHI) study of postmenopausal women, a lifetime history of breastfeeding for 12 months or more was associated with a 12% decrease in the risk of hypertension.⁵ For parous women, the prevalence of hypertension among breastfeeding (≥12 months) and never breastfeeding women was estimated to be 38.6% versus 42.1%.⁵ Similar results were observed in the Nurses’ Health Study II.⁶

Myocardial infarction and coronary heart disease

In the prospective Nurses’ Health Study, during 1,350,965 person-years of follow-up, 2,540 women had a myocardial infarction (MI). Women who had breastfed for ≥ 2 years had a 37% decreased risk of MI compared with women who never breastfed. After adjustment for family history, lifestyle factors, and adiposity, the observed reduction in risk was 23%.⁷ In the WHI (observational study plus controlled trial), women with a single live birth who breastfed for 7 to 12 months had a lower risk of cardiovascular disease than women with a single live birth who did not breastfeed (hazard ratio, 0.72; 95% confidence interval, 0.53–97).⁵

Breast cancer

In a systematic review and meta-analysis of 100 publications, breastfeeding >12 months reduced the risk of breast cancer by 26%.⁸ In a systematic review of 47 studies, the relative risk of breast cancer decreased by 4.7% for every 12 months of breastfeeding.⁹ In a systematic review and meta-analysis of 3 studies, ever breastfeeding was associated with a 28% reduced risk for triple-negative (ER-, PR-, HER2-) breast cancer among parous women.¹⁰ Triple-negative breast cancer generally has a poorer prognosis than receptor-positive breast cancers.

Continue to: Ovarian Cancer

In a systematic review and meta-analysis of 40 publications, ever breastfeeding was associated with a 37% reduction in the risk of ovarian cancer.⁸ In a prospective study of 1.1 million women in the United Kingdom, 8,719 developed ovarian cancer. Among parous women, ovarian cancer risk was reduced by 10% for every 12 months of breastfeeding.¹¹

Endometrial cancer

In a meta-analysis of 17 publications, including 8,981 cases and 17,241 controls, ever breastfeeding was associated with an 11% reduction in breast cancer risk.¹² In a meta-analysis of 15 publications with 6,704 cases, breastfeeding was associated with a 26% reduction in endometrial cancer. After controlling for hormone use and body mass index, the reduced risk was in the range of 35%. A linear relationship between breastfeeding and reduced risk of endometrial cancer was observed, with 1 month of breastfeeding being associated with a 1.2% reduction in the risk of endometrial cancer.¹³

Let’s support our patients’ health by encouraging successful breastfeeding

Obstetrician-gynecologists play an important role in helping women make informed decisions about breastfeeding. Most professional organizations, including the American College of Obstetricians and Gynecologists, recommend exclusive breastfeeding for the first 6 months of life, with continued breastfeeding and introduction of complementary food from 6 to 12 months.^14,15 Birth practices that help to increase successful breastfeeding include:

• inform all pregnant women about the newborn and maternal health benefits and management of breastfeeding
• initiate skin-to-skin contact at birth
• encourage the initiation of breastfeeding within 1 hour of birth
• ensure that breastfeeding newborns do not receive any food or drink other than breast milk, unless medically indicated
• encourage breastfeeding women to not use pacifiers or artificial nipples.¹⁵

When women are discharged from the maternity center, providing information about community-based lactation support is helpful in ensuring continuation of successful breastfeeding.¹⁶

Most patients know that exercise and maintaining a healthy weight can reduce the risk of developing many prevalent diseases. However, far fewer patients know that breastfeeding can reduce the risk of developing type 2 diabetes, hypertension, and coronary artery disease, as well as breast, ovarian, and endometrial cancers. Educating our patients about these health benefits may help them to more fully commit to breastfeeding.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Biosimilars for three widely used oncology drugs showed efficacy and safety in lung cancer and breast cancer similar to those of the reference products, according to findings reported at the 2018 annual meeting of the American Society of Clinical Oncology in Chicago.

Oncology biosimilars for bevacizumab (Avastin), trastuzumab (Herceptin), and filgrastim (Neupogen and others) have yielded positive results in various patient populations and clinical settings, investigators reported at the annual ASCO meeting. The findings advance the promise of new agents that have no clinically meaningful differences in efficacy and safety when compared with their reference drugs but have substantially lower cost.

“Biosimilars are here,” said Michael A Thompson, MD, PhD, of Aurora Health Care in Milwaukee, Wisconsin, “[although] issues remain, including clinical decision support and pathway adoption, naming differences across the world, competition and lower prices versus the illusion of a free market, and adoption to decrease costs and increase value to our patients.” Dr Thompson was commenting during an invited discussion at the meeting. He is the medical director of the Early Phase Cancer Research Program and the Oncology Precision Medicine Program at Aurora Health (also see Commentary at end of article).

Bevacizumab biosimilar

The REFLECTIONS trial (NCT02364999) was a multinational, first-line, randomized, controlled trial among 719 patients with advanced nonsquamous non–small-cell lung cancer (NSCLC). Patients were randomized to paclitaxel and carboplatin chemotherapy plus either bevacizumab (sourced from the European Union) or the candidate bevacizumab biosimilar PF-06439535 on a double-blind basis, followed by monotherapy with the same assigned agent.

The overall response rate by week 19, confirmed by week 25 – the trial’s primary endpoint – was 45.3% with the biosimilar and 44.6% with bevacizumab, reported lead author Mark A Socinski, MD, executive medical director of the Florida Hospital Cancer Institute in Orlando. The confidence interval (CI) for the risk difference fell within the equivalence margins set by European Union regulators (-13% and +13% for the 95% CI). And the confidence interval for the risk ratio fell within the equivalence margins set by the US Food and Drug Administration (0.73 and 1.37 for the 90% CI) and Japanese regulators (0.729 and 1.371 for the 95% CI).

Median progression-free survival (PFS) was 9.0 months with the biosimilar and 7.7 months with bevacizumab (hazard ratio [HR], 0.974; P = .814), and corresponding 1-year rates were 30.8% and 29.3%, respectively, Dr Socinski reported. Median overall survival was 18.4 months and 17.8 months (HR, 1.001; P = .991), and corresponding 1-year rates were 66.4% and 68.8%.

Rates of grade 3 or higher hypertension, cardiac disorders, and bleeding did not differ significantly with the 2 agents. Patients also had similar rates of grade 3 or higher serious adverse events (AEs) and of fatal (grade 5) serious AEs with the biosimilar and bevacizumab (5.3% and 5.9%, respectively).

“Similarity between PF-06439535 and bevacizumab-EU was demonstrated for the primary efficacy endpoint of overall response rate. ... There were no clinically meaningful differences in safety profile shown in this trial, and similar pharmacokinetic and immunogenicity results were seen across treatment groups,” Dr Socinski summarized. “These results confirm the similarity demonstrated in earlier analytical, nonclinical, and clinical studies of PF-06439535 with bevacizumab-EU.”

Funding Pfizer sponsored the REFLECTIONS trial. Disclosures Dr Socinski disclosed that his institution receives research funding from Pfizer. Source Socinski MA et al. A comparative clinical study of PF-06439535, a candidate bevacizumab biosimilar, and reference bevacizumab, in patients with advanced non-squamous non-small cell lung cancer. ASCO 2018, Abstract 109. https://meetinglibrary.asco.org/record/161702/abstract. Clinical trial registry number NCT02364999 https://clinicaltrials.gov/ct2/show/NCT02364999

Trastuzumab biosimilar

The phase 3 HERITAGE trial was a first-line, randomized, controlled trial that compared biosimilar trastuzumab-dkst (Ogivri) with trastuzumab in combination with taxane chemotherapy and then as maintenance monotherapy in 458 patients with HER2+ advanced breast cancer. The 24-week results, previously reported (JAMA. 2017 Jan 3;317[1]:37-47), showed a similar overall response rate with each agent when combined with chemotherapy. Rates of various AEs were essentially the same.

The 48-week results showed a median PFS of 11.1 months with trastuzumab-dkst and 11.1 months with trastuzumab (HR, 0.95; P = .842), reported senior investigator Hope S Rugo, MD, a clinical professor of medicine and director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center. “The overall survival is immature but is impressive at over 80% at 52 weeks,” she noted.

Presence of overall response at 24 weeks correlated with duration of PFS at 48 weeks (biserial r = .752). “Additional patients achieved a response during the monotherapy portion of the treatment, which is intriguing and clearly emphasizes the importance of monotherapy, as well as the importance of having alternate agents at lower cost available,” Dr Rugo commented.

Common AEs through week 48 were much the same as those seen at week 24, with few additional [events] occurring during monotherapy. “No new safety issues were observed, and in fact, toxicity during monotherapy was quite minor,” she noted. “One thing that’s interesting here is that there was more arthralgia during the first 24 weeks with trastuzumab-dkst than with trastuzumab, but in monotherapy, this fell to a very low number and was identical between the 2 arms. Paclitaxel, which people stayed on for longer [with the biosimilar], may have been the cause of this.”

The 48-week rates of AEs of special interest – respiratory events, cardiac disorders, and infusion-related AEs – and of serious AEs were similar for the 2 agents.

“We didn’t see any additional serious cardiac events during monotherapy,” Dr Rugo noted. Mean and median left ventricular ejection fraction over 48 weeks were similar, as was the rate of LVEF, which dropped below 50% (4.0% with trastuzumab-dkst and 3.3% with trastuzumab). The incidences of antidrug antibody and neutralizing antibody were also comparably low in both groups.

“HERITAGE data, now at week 48, supports trastuzumab-dkst as a biosimilar to trastuzumab in all approved indications,” Dr Rugo said. “Final overall survival will be assessed after 36 months or after 240 deaths, whichever occurs first. Based on current data, this is predicted to conclude by the end of 2018, with final overall survival data available next year.”

Dr Rugo emphasized that trastuzumab-dkst provides “an additional high-quality treatment option for patients with HER2+ breast cancers in any setting. This study shows that biosimilars offer the potential for worldwide cost savings and improved access to life-saving therapies. It’s sobering to think that the patients enrolled in this study would not otherwise have had access to continued trastuzumab therapy, and so many of them are still alive with longer follow-up.”

Funding Mylan sponsored the HERITAGE trial. Disclosures Dr Rugo disclosed that she receives travel, accommodations, and/or expenses from Mylan. Source Manikhas A et al. Biosimilar trastuzumab-dkst monotherapy versus trastuzumab monotherapy after combination therapy: Toxicity, efficacy, and immunogenicity from the phase 3 Heritage trial. ASCO 2018, Abstract 110. https://meetinglibrary.asco.org/record/161572/abstract. Clinical trial registry number NCT02472964 https://clinicaltrials.gov/ct2/show/NCT02472964
 

Filgrastim biosimilar

Investigators led by Nadia Harbeck, MD, PhD, head of the Breast Center and chair for Conservative Oncology in the department of OB&GYN at the University of Munich (Germany), compared efficacy of filgrastim-sndz (Zarxio), a biosimilar of filgrastim (recombinant granulocyte colony-stimulating factor, or G-CSF), in a trial population with that of a real-world population of women receiving chemotherapy for breast cancer.

Data for the former came from PIONEER, a phase 3, randomized, controlled trial among patients with nonmetastatic breast cancer undergoing docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy in the neoadjuvant or adjuvant setting (Ann Oncol. 2015;26[9]:1948-53). Data for the latter came from MONITOR-GCSF, a postmarketing, open-label, observational cohort study among patients from 12 European countries receiving chemotherapy for various solid and hematologic malignancies (Support Care Cancer. 2016;24[2]:911-25).

Dr Harbeck and her colleagues compared 217 women who had nonmetastatic breast cancer from the trial with 466 women who had any-stage breast cancer (42% metastatic) from the real-world cohort.

Results showed that the 6.2% rate of chemotherapy-induced febrile neutropenia in any cycle seen in the real-world population was much the same as the 5.1% rate seen previously in the trial/biosimilar population. Findings were similar for temperature exceeding 38.5°C in any cycle: 3.4% and 5.6%, respectively. The real-world population had a lower rate of severe neutropenia than did the trial population (19.5% and 74.3%) and higher rates of infection (15.5% and 7.9%) and hospitalization caused by febrile neutropenia (3.9% and 1.8%). Findings were essentially the same in cycle-level analyses.

The real-world cohort had many fewer any-severity safety events of special interest than did the trial cohort, such as musculoskeletal/connective tissue disorders (20 and 261 events, respectively) and skin/subcutaneous tissue disorders (5 and 258 events). “Seeing these data, you have to keep in mind that the patients received totally different chemotherapy. TAC chemotherapy has a lot of chemotherapy-associated side effects,” Dr Harbeck noted. “The other thing is that MONITOR was a real-world database, and one could assume that there is some underreporting of events that are not directly correlated to the events that are of particular interest.”

Additional results available only from the trial showed that no patients developed binding or neutralizing antibodies against G-CSF.

“From a clinician’s point of view, it is very reassuring that we did not see any other safety signals in the real-world data than we saw in the randomized controlled trial and the efficacy was very, very similar,” Dr Harbeck commented. “Having seen the discrepancies in the data, I think it’s important to have randomized controlled trials to assess and monitor AEs for registration purposes and real-world evidence to reflect the daily clinical routine,” she concluded.
 

Funding Sandoz sponsored the PIONEER and MONITOR-GCSF trials. Disclosures Dr Harbeck disclosed that she has a consulting or advisory role with Sandoz. Source Harbeck N et al. Comparison of efficacy and safety of biosimilar filgrastim in a RCT (PIONEER) and real-world practice (MONITOR-GCSF). ASCO 2018, Abstract 111. https://meetinglibrary.asco.org/record/161688/abstract. Clinical trial registry number NCT01519700 https://clinicaltrials.gov/ct2/show/NCT01519700

Biosimilars for three widely used oncology drugs showed efficacy and safety in lung cancer and breast cancer similar to those of the reference products, according to findings reported at the 2018 annual meeting of the American Society of Clinical Oncology in Chicago.

Oncology biosimilars for bevacizumab (Avastin), trastuzumab (Herceptin), and filgrastim (Neupogen and others) have yielded positive results in various patient populations and clinical settings, investigators reported at the annual ASCO meeting. The findings advance the promise of new agents that have no clinically meaningful differences in efficacy and safety when compared with their reference drugs but have substantially lower cost.

“Biosimilars are here,” said Michael A Thompson, MD, PhD, of Aurora Health Care in Milwaukee, Wisconsin, “[although] issues remain, including clinical decision support and pathway adoption, naming differences across the world, competition and lower prices versus the illusion of a free market, and adoption to decrease costs and increase value to our patients.” Dr Thompson was commenting during an invited discussion at the meeting. He is the medical director of the Early Phase Cancer Research Program and the Oncology Precision Medicine Program at Aurora Health (also see Commentary at end of article).

Bevacizumab biosimilar

The REFLECTIONS trial (NCT02364999) was a multinational, first-line, randomized, controlled trial among 719 patients with advanced nonsquamous non–small-cell lung cancer (NSCLC). Patients were randomized to paclitaxel and carboplatin chemotherapy plus either bevacizumab (sourced from the European Union) or the candidate bevacizumab biosimilar PF-06439535 on a double-blind basis, followed by monotherapy with the same assigned agent.

The overall response rate by week 19, confirmed by week 25 – the trial’s primary endpoint – was 45.3% with the biosimilar and 44.6% with bevacizumab, reported lead author Mark A Socinski, MD, executive medical director of the Florida Hospital Cancer Institute in Orlando. The confidence interval (CI) for the risk difference fell within the equivalence margins set by European Union regulators (-13% and +13% for the 95% CI). And the confidence interval for the risk ratio fell within the equivalence margins set by the US Food and Drug Administration (0.73 and 1.37 for the 90% CI) and Japanese regulators (0.729 and 1.371 for the 95% CI).

Median progression-free survival (PFS) was 9.0 months with the biosimilar and 7.7 months with bevacizumab (hazard ratio [HR], 0.974; P = .814), and corresponding 1-year rates were 30.8% and 29.3%, respectively, Dr Socinski reported. Median overall survival was 18.4 months and 17.8 months (HR, 1.001; P = .991), and corresponding 1-year rates were 66.4% and 68.8%.

Rates of grade 3 or higher hypertension, cardiac disorders, and bleeding did not differ significantly with the 2 agents. Patients also had similar rates of grade 3 or higher serious adverse events (AEs) and of fatal (grade 5) serious AEs with the biosimilar and bevacizumab (5.3% and 5.9%, respectively).

“Similarity between PF-06439535 and bevacizumab-EU was demonstrated for the primary efficacy endpoint of overall response rate. ... There were no clinically meaningful differences in safety profile shown in this trial, and similar pharmacokinetic and immunogenicity results were seen across treatment groups,” Dr Socinski summarized. “These results confirm the similarity demonstrated in earlier analytical, nonclinical, and clinical studies of PF-06439535 with bevacizumab-EU.”

Funding Pfizer sponsored the REFLECTIONS trial. Disclosures Dr Socinski disclosed that his institution receives research funding from Pfizer. Source Socinski MA et al. A comparative clinical study of PF-06439535, a candidate bevacizumab biosimilar, and reference bevacizumab, in patients with advanced non-squamous non-small cell lung cancer. ASCO 2018, Abstract 109. https://meetinglibrary.asco.org/record/161702/abstract. Clinical trial registry number NCT02364999 https://clinicaltrials.gov/ct2/show/NCT02364999

Trastuzumab biosimilar

The phase 3 HERITAGE trial was a first-line, randomized, controlled trial that compared biosimilar trastuzumab-dkst (Ogivri) with trastuzumab in combination with taxane chemotherapy and then as maintenance monotherapy in 458 patients with HER2+ advanced breast cancer. The 24-week results, previously reported (JAMA. 2017 Jan 3;317[1]:37-47), showed a similar overall response rate with each agent when combined with chemotherapy. Rates of various AEs were essentially the same.

The 48-week results showed a median PFS of 11.1 months with trastuzumab-dkst and 11.1 months with trastuzumab (HR, 0.95; P = .842), reported senior investigator Hope S Rugo, MD, a clinical professor of medicine and director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center. “The overall survival is immature but is impressive at over 80% at 52 weeks,” she noted.

Presence of overall response at 24 weeks correlated with duration of PFS at 48 weeks (biserial r = .752). “Additional patients achieved a response during the monotherapy portion of the treatment, which is intriguing and clearly emphasizes the importance of monotherapy, as well as the importance of having alternate agents at lower cost available,” Dr Rugo commented.

Common AEs through week 48 were much the same as those seen at week 24, with few additional [events] occurring during monotherapy. “No new safety issues were observed, and in fact, toxicity during monotherapy was quite minor,” she noted. “One thing that’s interesting here is that there was more arthralgia during the first 24 weeks with trastuzumab-dkst than with trastuzumab, but in monotherapy, this fell to a very low number and was identical between the 2 arms. Paclitaxel, which people stayed on for longer [with the biosimilar], may have been the cause of this.”

The 48-week rates of AEs of special interest – respiratory events, cardiac disorders, and infusion-related AEs – and of serious AEs were similar for the 2 agents.

“We didn’t see any additional serious cardiac events during monotherapy,” Dr Rugo noted. Mean and median left ventricular ejection fraction over 48 weeks were similar, as was the rate of LVEF, which dropped below 50% (4.0% with trastuzumab-dkst and 3.3% with trastuzumab). The incidences of antidrug antibody and neutralizing antibody were also comparably low in both groups.

“HERITAGE data, now at week 48, supports trastuzumab-dkst as a biosimilar to trastuzumab in all approved indications,” Dr Rugo said. “Final overall survival will be assessed after 36 months or after 240 deaths, whichever occurs first. Based on current data, this is predicted to conclude by the end of 2018, with final overall survival data available next year.”

Dr Rugo emphasized that trastuzumab-dkst provides “an additional high-quality treatment option for patients with HER2+ breast cancers in any setting. This study shows that biosimilars offer the potential for worldwide cost savings and improved access to life-saving therapies. It’s sobering to think that the patients enrolled in this study would not otherwise have had access to continued trastuzumab therapy, and so many of them are still alive with longer follow-up.”

Funding Mylan sponsored the HERITAGE trial. Disclosures Dr Rugo disclosed that she receives travel, accommodations, and/or expenses from Mylan. Source Manikhas A et al. Biosimilar trastuzumab-dkst monotherapy versus trastuzumab monotherapy after combination therapy: Toxicity, efficacy, and immunogenicity from the phase 3 Heritage trial. ASCO 2018, Abstract 110. https://meetinglibrary.asco.org/record/161572/abstract. Clinical trial registry number NCT02472964 https://clinicaltrials.gov/ct2/show/NCT02472964
 

Filgrastim biosimilar

Investigators led by Nadia Harbeck, MD, PhD, head of the Breast Center and chair for Conservative Oncology in the department of OB&GYN at the University of Munich (Germany), compared efficacy of filgrastim-sndz (Zarxio), a biosimilar of filgrastim (recombinant granulocyte colony-stimulating factor, or G-CSF), in a trial population with that of a real-world population of women receiving chemotherapy for breast cancer.

Data for the former came from PIONEER, a phase 3, randomized, controlled trial among patients with nonmetastatic breast cancer undergoing docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy in the neoadjuvant or adjuvant setting (Ann Oncol. 2015;26[9]:1948-53). Data for the latter came from MONITOR-GCSF, a postmarketing, open-label, observational cohort study among patients from 12 European countries receiving chemotherapy for various solid and hematologic malignancies (Support Care Cancer. 2016;24[2]:911-25).

Dr Harbeck and her colleagues compared 217 women who had nonmetastatic breast cancer from the trial with 466 women who had any-stage breast cancer (42% metastatic) from the real-world cohort.

Results showed that the 6.2% rate of chemotherapy-induced febrile neutropenia in any cycle seen in the real-world population was much the same as the 5.1% rate seen previously in the trial/biosimilar population. Findings were similar for temperature exceeding 38.5°C in any cycle: 3.4% and 5.6%, respectively. The real-world population had a lower rate of severe neutropenia than did the trial population (19.5% and 74.3%) and higher rates of infection (15.5% and 7.9%) and hospitalization caused by febrile neutropenia (3.9% and 1.8%). Findings were essentially the same in cycle-level analyses.

The real-world cohort had many fewer any-severity safety events of special interest than did the trial cohort, such as musculoskeletal/connective tissue disorders (20 and 261 events, respectively) and skin/subcutaneous tissue disorders (5 and 258 events). “Seeing these data, you have to keep in mind that the patients received totally different chemotherapy. TAC chemotherapy has a lot of chemotherapy-associated side effects,” Dr Harbeck noted. “The other thing is that MONITOR was a real-world database, and one could assume that there is some underreporting of events that are not directly correlated to the events that are of particular interest.”

Additional results available only from the trial showed that no patients developed binding or neutralizing antibodies against G-CSF.

“From a clinician’s point of view, it is very reassuring that we did not see any other safety signals in the real-world data than we saw in the randomized controlled trial and the efficacy was very, very similar,” Dr Harbeck commented. “Having seen the discrepancies in the data, I think it’s important to have randomized controlled trials to assess and monitor AEs for registration purposes and real-world evidence to reflect the daily clinical routine,” she concluded.
 

Funding Sandoz sponsored the PIONEER and MONITOR-GCSF trials. Disclosures Dr Harbeck disclosed that she has a consulting or advisory role with Sandoz. Source Harbeck N et al. Comparison of efficacy and safety of biosimilar filgrastim in a RCT (PIONEER) and real-world practice (MONITOR-GCSF). ASCO 2018, Abstract 111. https://meetinglibrary.asco.org/record/161688/abstract. Clinical trial registry number NCT01519700 https://clinicaltrials.gov/ct2/show/NCT01519700

Biosimilars for three widely used oncology drugs showed efficacy and safety in lung cancer and breast cancer similar to those of the reference products, according to findings reported at the 2018 annual meeting of the American Society of Clinical Oncology in Chicago.

Oncology biosimilars for bevacizumab (Avastin), trastuzumab (Herceptin), and filgrastim (Neupogen and others) have yielded positive results in various patient populations and clinical settings, investigators reported at the annual ASCO meeting. The findings advance the promise of new agents that have no clinically meaningful differences in efficacy and safety when compared with their reference drugs but have substantially lower cost.

“Biosimilars are here,” said Michael A Thompson, MD, PhD, of Aurora Health Care in Milwaukee, Wisconsin, “[although] issues remain, including clinical decision support and pathway adoption, naming differences across the world, competition and lower prices versus the illusion of a free market, and adoption to decrease costs and increase value to our patients.” Dr Thompson was commenting during an invited discussion at the meeting. He is the medical director of the Early Phase Cancer Research Program and the Oncology Precision Medicine Program at Aurora Health (also see Commentary at end of article).

Bevacizumab biosimilar

The REFLECTIONS trial (NCT02364999) was a multinational, first-line, randomized, controlled trial among 719 patients with advanced nonsquamous non–small-cell lung cancer (NSCLC). Patients were randomized to paclitaxel and carboplatin chemotherapy plus either bevacizumab (sourced from the European Union) or the candidate bevacizumab biosimilar PF-06439535 on a double-blind basis, followed by monotherapy with the same assigned agent.

The overall response rate by week 19, confirmed by week 25 – the trial’s primary endpoint – was 45.3% with the biosimilar and 44.6% with bevacizumab, reported lead author Mark A Socinski, MD, executive medical director of the Florida Hospital Cancer Institute in Orlando. The confidence interval (CI) for the risk difference fell within the equivalence margins set by European Union regulators (-13% and +13% for the 95% CI). And the confidence interval for the risk ratio fell within the equivalence margins set by the US Food and Drug Administration (0.73 and 1.37 for the 90% CI) and Japanese regulators (0.729 and 1.371 for the 95% CI).

Median progression-free survival (PFS) was 9.0 months with the biosimilar and 7.7 months with bevacizumab (hazard ratio [HR], 0.974; P = .814), and corresponding 1-year rates were 30.8% and 29.3%, respectively, Dr Socinski reported. Median overall survival was 18.4 months and 17.8 months (HR, 1.001; P = .991), and corresponding 1-year rates were 66.4% and 68.8%.

Rates of grade 3 or higher hypertension, cardiac disorders, and bleeding did not differ significantly with the 2 agents. Patients also had similar rates of grade 3 or higher serious adverse events (AEs) and of fatal (grade 5) serious AEs with the biosimilar and bevacizumab (5.3% and 5.9%, respectively).

“Similarity between PF-06439535 and bevacizumab-EU was demonstrated for the primary efficacy endpoint of overall response rate. ... There were no clinically meaningful differences in safety profile shown in this trial, and similar pharmacokinetic and immunogenicity results were seen across treatment groups,” Dr Socinski summarized. “These results confirm the similarity demonstrated in earlier analytical, nonclinical, and clinical studies of PF-06439535 with bevacizumab-EU.”

Funding Pfizer sponsored the REFLECTIONS trial. Disclosures Dr Socinski disclosed that his institution receives research funding from Pfizer. Source Socinski MA et al. A comparative clinical study of PF-06439535, a candidate bevacizumab biosimilar, and reference bevacizumab, in patients with advanced non-squamous non-small cell lung cancer. ASCO 2018, Abstract 109. https://meetinglibrary.asco.org/record/161702/abstract. Clinical trial registry number NCT02364999 https://clinicaltrials.gov/ct2/show/NCT02364999

Trastuzumab biosimilar

The phase 3 HERITAGE trial was a first-line, randomized, controlled trial that compared biosimilar trastuzumab-dkst (Ogivri) with trastuzumab in combination with taxane chemotherapy and then as maintenance monotherapy in 458 patients with HER2+ advanced breast cancer. The 24-week results, previously reported (JAMA. 2017 Jan 3;317[1]:37-47), showed a similar overall response rate with each agent when combined with chemotherapy. Rates of various AEs were essentially the same.

The 48-week results showed a median PFS of 11.1 months with trastuzumab-dkst and 11.1 months with trastuzumab (HR, 0.95; P = .842), reported senior investigator Hope S Rugo, MD, a clinical professor of medicine and director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center. “The overall survival is immature but is impressive at over 80% at 52 weeks,” she noted.

Presence of overall response at 24 weeks correlated with duration of PFS at 48 weeks (biserial r = .752). “Additional patients achieved a response during the monotherapy portion of the treatment, which is intriguing and clearly emphasizes the importance of monotherapy, as well as the importance of having alternate agents at lower cost available,” Dr Rugo commented.

Common AEs through week 48 were much the same as those seen at week 24, with few additional [events] occurring during monotherapy. “No new safety issues were observed, and in fact, toxicity during monotherapy was quite minor,” she noted. “One thing that’s interesting here is that there was more arthralgia during the first 24 weeks with trastuzumab-dkst than with trastuzumab, but in monotherapy, this fell to a very low number and was identical between the 2 arms. Paclitaxel, which people stayed on for longer [with the biosimilar], may have been the cause of this.”

The 48-week rates of AEs of special interest – respiratory events, cardiac disorders, and infusion-related AEs – and of serious AEs were similar for the 2 agents.

“We didn’t see any additional serious cardiac events during monotherapy,” Dr Rugo noted. Mean and median left ventricular ejection fraction over 48 weeks were similar, as was the rate of LVEF, which dropped below 50% (4.0% with trastuzumab-dkst and 3.3% with trastuzumab). The incidences of antidrug antibody and neutralizing antibody were also comparably low in both groups.

“HERITAGE data, now at week 48, supports trastuzumab-dkst as a biosimilar to trastuzumab in all approved indications,” Dr Rugo said. “Final overall survival will be assessed after 36 months or after 240 deaths, whichever occurs first. Based on current data, this is predicted to conclude by the end of 2018, with final overall survival data available next year.”

Dr Rugo emphasized that trastuzumab-dkst provides “an additional high-quality treatment option for patients with HER2+ breast cancers in any setting. This study shows that biosimilars offer the potential for worldwide cost savings and improved access to life-saving therapies. It’s sobering to think that the patients enrolled in this study would not otherwise have had access to continued trastuzumab therapy, and so many of them are still alive with longer follow-up.”

Funding Mylan sponsored the HERITAGE trial. Disclosures Dr Rugo disclosed that she receives travel, accommodations, and/or expenses from Mylan. Source Manikhas A et al. Biosimilar trastuzumab-dkst monotherapy versus trastuzumab monotherapy after combination therapy: Toxicity, efficacy, and immunogenicity from the phase 3 Heritage trial. ASCO 2018, Abstract 110. https://meetinglibrary.asco.org/record/161572/abstract. Clinical trial registry number NCT02472964 https://clinicaltrials.gov/ct2/show/NCT02472964
 

Filgrastim biosimilar

Investigators led by Nadia Harbeck, MD, PhD, head of the Breast Center and chair for Conservative Oncology in the department of OB&GYN at the University of Munich (Germany), compared efficacy of filgrastim-sndz (Zarxio), a biosimilar of filgrastim (recombinant granulocyte colony-stimulating factor, or G-CSF), in a trial population with that of a real-world population of women receiving chemotherapy for breast cancer.

Data for the former came from PIONEER, a phase 3, randomized, controlled trial among patients with nonmetastatic breast cancer undergoing docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy in the neoadjuvant or adjuvant setting (Ann Oncol. 2015;26[9]:1948-53). Data for the latter came from MONITOR-GCSF, a postmarketing, open-label, observational cohort study among patients from 12 European countries receiving chemotherapy for various solid and hematologic malignancies (Support Care Cancer. 2016;24[2]:911-25).

Dr Harbeck and her colleagues compared 217 women who had nonmetastatic breast cancer from the trial with 466 women who had any-stage breast cancer (42% metastatic) from the real-world cohort.

Results showed that the 6.2% rate of chemotherapy-induced febrile neutropenia in any cycle seen in the real-world population was much the same as the 5.1% rate seen previously in the trial/biosimilar population. Findings were similar for temperature exceeding 38.5°C in any cycle: 3.4% and 5.6%, respectively. The real-world population had a lower rate of severe neutropenia than did the trial population (19.5% and 74.3%) and higher rates of infection (15.5% and 7.9%) and hospitalization caused by febrile neutropenia (3.9% and 1.8%). Findings were essentially the same in cycle-level analyses.

The real-world cohort had many fewer any-severity safety events of special interest than did the trial cohort, such as musculoskeletal/connective tissue disorders (20 and 261 events, respectively) and skin/subcutaneous tissue disorders (5 and 258 events). “Seeing these data, you have to keep in mind that the patients received totally different chemotherapy. TAC chemotherapy has a lot of chemotherapy-associated side effects,” Dr Harbeck noted. “The other thing is that MONITOR was a real-world database, and one could assume that there is some underreporting of events that are not directly correlated to the events that are of particular interest.”

Additional results available only from the trial showed that no patients developed binding or neutralizing antibodies against G-CSF.

“From a clinician’s point of view, it is very reassuring that we did not see any other safety signals in the real-world data than we saw in the randomized controlled trial and the efficacy was very, very similar,” Dr Harbeck commented. “Having seen the discrepancies in the data, I think it’s important to have randomized controlled trials to assess and monitor AEs for registration purposes and real-world evidence to reflect the daily clinical routine,” she concluded.
 

Funding Sandoz sponsored the PIONEER and MONITOR-GCSF trials. Disclosures Dr Harbeck disclosed that she has a consulting or advisory role with Sandoz. Source Harbeck N et al. Comparison of efficacy and safety of biosimilar filgrastim in a RCT (PIONEER) and real-world practice (MONITOR-GCSF). ASCO 2018, Abstract 111. https://meetinglibrary.asco.org/record/161688/abstract. Clinical trial registry number NCT01519700 https://clinicaltrials.gov/ct2/show/NCT01519700

About 12.4% of women in the United States will be diagnosed with breast cancer at some point in their lifetime.¹ A percentage of these women will develop metastatic disease and are estimated to have a 5-year survival rate of 22%.² There have been meaningful improvements in survival because of earlier detection and more effective systemic therapies. Patients with hormone-sensitive disease often respond to endocrine therapy, and this frequently represents front-line treatment for these patients, resulting in palliation of symptoms while maintaining quality of life.

However, endocrine resistance inevitably occurs, and a great deal of research has been focused on developing strategies to combat resistance. One mechanism of endocrine resistance is though the Cyclin-dependent kinases 4 and 6 (CDK4/6) complexes. Among the most promising of the strategies to prevent resistance are the CDK4/6 inhibitors. There are now 3 approved CDK4/6 inhibitor drugs that can be used in combination with endocrine therapy, 1 of which can also be used as a single agent. When used in combination with endocrine therapy, the use of CDK 4/6 inhibitors has significantly improved progression-free survival (PFS) in patients with hormone-sensitive HER2-negative metastatic breast cancer by inhibiting cellular division and growth.³ In postmenopausal women, endocrine therapy plus CDK4/6 inhibitors are the preferred first-line regimen for metastatic disease.

Since the approval of palbociclib by the US Food and Drug Administration in 2015, the most common hematologic lab abnormalities are anemia, leukopenia, neutropenia, and thrombocytopenia. The most common nonhematologic adverse events (AEs) are fatigue, infection, nausea, and stomatitis. Hepatic toxicity has not been commonly observed. We report here the case of a 57-year-old woman on palbociclib and fulvestrant who developed significant elevation of liver function tests after starting palbociclib, suggesting a possible drug-induced liver injury from palbociclib.
 

Case presentation and summary

A 57-year-old woman with history of hypothyroidism and hypertension presented in May 2016 with a lump in her right breast and back pain. The lump was biopsied and revealed invasive ductal carcinoma, moderately differentiated, estrogen receptor (ER) positive 100%, progesterone receptor (PR) positive 95%, and HER2 negative. A positron emission tomography (PET)–computed tomography (CT) scan and magnetic resonance imaging showed bone metastasis at several vertebral levels, and the results of a bone biopsy confirmed metastatic adenocarcinoma of breast origin, ER positive 60%, PR positive 40%, and HER2 negative. No liver lesions were seen on imaging, but there was suggestion of fatty liver. She was started on letrozole 2.5 mg daily in July 2016 while undergoing kyphoplasty and subsequent radiation. A restaging PET scan revealed progression of disease on letrozole, with possible new rib lesion and progression in the breast. No liver disease was noted. Therapy was changed to fulvestrant and palbociclib. Fulvestrant was started in March 2017 with standard dosing of 500 mg intramuscular on days 1, 15, and 29, and then once a month thereafter. Her first cycle of palbociclib was started on April 5, dosed at 125 mg by mouth daily for 21 days, followed by 7 days off, repeated every 28 days (all dates hereinafter fell within 2017, unless otherwise stipulated).

Labs checked on April 28 and May 26 were unremarkable. A restaging CT scan of the chest, abdomen, and pelvis was done on June 21 after completion of 3 cycles of fulvestrant and palbociclib. There was no evidence of liver metastases, only the fatty infiltration of the liver that had been seen previously. On June 23, 2017, lab results showed a transaminitis with an alanine aminotransferase (ALT) level of 446 IU/L (reference range 10-33 IU/L) and aspartate aminotransferase (AST) level of 183 IU/L (reference range 0-32 IU/L).

The patient’s liver enzyme levels continued to increase and peaked on July 3 at ALT >700 IU/L and AST at 421 IU/L. Her total bilirubin and alkaline phosphatase levels remained within normal limits. She had received her final dose of fulvestrant on May 31 and had taken her last dose of palbociclib on June 20, 2017. She had no history of elevated liver enzymes or liver disease, although the initial PET scan done at diagnosis had suggested hepatic steatosis. She said she had not recently used antibiotics, alcohol, or over-the-counter medications or supplements. There was no family history of liver problems, inflammatory bowel disease, or gastrointestinal malignancy. The only other medications she had taken recently were denosumab, levothyroxine for hypothyroidism, and amlodipine for hypertension. She was seen by hepatology for evaluation of acute hepatitis. Other etiologies for her elevated liver enzymes were ruled out, and she was diagnosed with a drug-induced liver injury from one of her anticancer medications. Her treatments with fulvestrant and palbociclib were held, and the results of her liver function tests normalized by September 2017.

Fulvestrant was restarted on August 24, and her lab results remained normal through November of that year, when restaging scans showed progression with new axillary adenopathy suspicious for metastasis. Imaging also showed a 1.6-cm hepatic lesion suggestive of a focal area of fat deposition or atypical hemangioma without definitive evidence of metastasis. Follow-up imaging was recommended. She was therefore rechallenged with palbociclib at a reduced dose of 100 mg by mouth daily and received the first dose on November 30. On December 8, repeat labs again showed elevated liver function tests (ALT, 285 IU/L; AST, 112 IU/L). Treatment with palbociclib was discontinued on December 10. Because the patient was not able to tolerate palbociclib, and fulvestrant alone was not controlling the disease, she was started on an alternate endocrine therapy with tamoxifen on December 26. The patient’s liver function tests normalized again by January 2018.
 

Discussion

The use of targeted therapies has changed the landscape of oncologic treatments. Several studies have evaluated the safety and efficacy of palbociclib in combination with endocrine therapy. The Palbociclib Ongoing Trials in the Management of Breast Cancer (PALOMA)-1 study, an open-label, randomized, phase-2 trial involving patients with newly diagnosed metastatic hormone sensitive HER2-negative breast cancer, demonstrated that palbociclib in combination with letrozole was associated with significantly longer PFS than letrozole alone.⁴ These results were later confirmed in the larger PALOMA-2 study, a randomized, double-blind, phase-3 trial that evaluated 666 postmenopausal patients with no prior systemic therapy. In that study, median PFS for the palbociclib–letrozole group was 24.8 months, compared with 14.5 months for the letrozole-alone group (hazard ratio [HR] for disease progression or death, 0.58 [0.46–0.72], P < .001).⁵ The most recent PALOMA-3 study, a phase-3 trial involving 521 patients with advanced hormone receptor–positive, HER2-negative breast cancer that had progressed during initial endocrine therapy, evaluated the efficacy of combined palbociclib and fulvestrant in a randomized, double-blind, placebo-controlled, parallel-group trial. The result was that the palbociclib–fulvestrant combination resulted in longer median PFS of 9.2 months, compared with 3.8 months with fulvestrant alone (P < .001).⁶

These trials also monitored the number of AEs as secondary aims. The most commonly reported AEs in the PALOMA trials for those patients in the palbociclib group were hematologic, with neutropenia being the most common, followed by leukopenia, anemia, and thrombocytopenia. The most common nonhematologic AEs reported in the palbociclib-fulvestrant group were fatigue, nausea, and headache. Elevated liver function tests were a rare but reported AE in 7.2% of the palbociclib-treated patients in the PALOMA-1 study.⁷ In the PALOMA-2 study, ALT and AST elevations were reported as AEs (all grades) in 9.9% and 9.7% of palbociclib-treated patients, respectively.⁵ In the PALOMA-3 study, there was 1 fatal serious AE of hepatic failure with grade 5 disease progression in the palbociclib group; however, the patient’s medical history included progressive liver metastasis and disease progression.⁶ A pooled safety analysis conducted across all PALOMA studies demonstrated that grade 3/4 AST and ALT elevations occurred in 3.3% and 2.3% of palbociclib-treated patients, respectively, again highlighting a reported but rare occurrence.⁸

The patient described in the present case report started on combination fulvestrant and palbociclib after her disease showed progression on letrozole. She developed an increase in transaminases after completing 3 cycles of palbociclib. Liver function tests increased nearly 12 weeks after beginning her first cycle of the CDK 4/6 inhibitor. Staging scans of the patient demonstrated fatty liver. It is not known if her fatty liver contributed to her transminitis; however, her baseline labs showed normal liver function tests, and they did not increase until after therapy with fulvestrant–palbociclib was started. It might have been that her fatty liver caused her to be at higher risk of transaminitis with administration of palbociclib, although we cannot be certain. Her lab results remained normal while she was on fulvestrant alone, and the liver function test results increased only after palbociclib was started, making this drug the more likely culprit.

Both events of increased liver enzymes occurred within a week of the last palbociclib dose; however, we note that hepatotoxicity developed at a faster rate when the patient was rechallenged with palbociclib at a lower dose, with elevated liver function tests increasing 1 week after restarting treatment as opposed to the first episode that occurred after 3 cycles of the palbociclib. After discontinuation of the medication, liver function tests again normalized, suggesting that palbociclib was most likely the causative agent. In addition, the degree of elevated liver enzymes was less severe on re-exposure at the lower dose of 100 mg, which raises the possibility that there could be a dose-dependent association between palbociclib and hepatotoxicity. There have been few case reports of increased liver enzymes associated with palbociclib, and it is only recently that this association has been more recognized. A meta-analysis by Zaw and colleagues has demonstrated that CDK 4/6 inhibitor–based regimens are associated with a higher risk of elevated AST and ALT; however, their relation with dose dependence was not described. In particular, they found that CDK 4/6 inhibitors increased the risk of high-grade, elevated ALT with a relative risk of 4.33 (95% confidence interval, 2.15-8.71; P < .0001). The meta-analysis also included other CDK 4/6 inhibitors such as abemaciclib and ribociclib, which have been more commonly associated with liver toxicity than palbociclib has.⁹ Our case report highlights the specific association between palbociclib and elevated liver enzymes.

In conclusion, this case report illustrates that our patient’s elevated liver enzymes were likely related to palbociclib. This is further supported by the fact that this AE occurred twice, both times after palbociclib exposure. In each instance, liver enzymes normalized after discontinuation of palbociclib. One cannot entirely rule out that fulvestrant might have been the culprit medication, but the patient’s normal hepatic panel for several months after starting fulvestrant suggests that is less likely. This case report is indicative of an uncommon complication in the treatment of metastatic breast cancer, one that is starting to gain more recognition, and we must think of palbociclib as a possible cause of drug-induced liver injury when targeted CDK 4/6–based regimens are used.

About 12.4% of women in the United States will be diagnosed with breast cancer at some point in their lifetime.¹ A percentage of these women will develop metastatic disease and are estimated to have a 5-year survival rate of 22%.² There have been meaningful improvements in survival because of earlier detection and more effective systemic therapies. Patients with hormone-sensitive disease often respond to endocrine therapy, and this frequently represents front-line treatment for these patients, resulting in palliation of symptoms while maintaining quality of life.

However, endocrine resistance inevitably occurs, and a great deal of research has been focused on developing strategies to combat resistance. One mechanism of endocrine resistance is though the Cyclin-dependent kinases 4 and 6 (CDK4/6) complexes. Among the most promising of the strategies to prevent resistance are the CDK4/6 inhibitors. There are now 3 approved CDK4/6 inhibitor drugs that can be used in combination with endocrine therapy, 1 of which can also be used as a single agent. When used in combination with endocrine therapy, the use of CDK 4/6 inhibitors has significantly improved progression-free survival (PFS) in patients with hormone-sensitive HER2-negative metastatic breast cancer by inhibiting cellular division and growth.³ In postmenopausal women, endocrine therapy plus CDK4/6 inhibitors are the preferred first-line regimen for metastatic disease.

Since the approval of palbociclib by the US Food and Drug Administration in 2015, the most common hematologic lab abnormalities are anemia, leukopenia, neutropenia, and thrombocytopenia. The most common nonhematologic adverse events (AEs) are fatigue, infection, nausea, and stomatitis. Hepatic toxicity has not been commonly observed. We report here the case of a 57-year-old woman on palbociclib and fulvestrant who developed significant elevation of liver function tests after starting palbociclib, suggesting a possible drug-induced liver injury from palbociclib.
 

Case presentation and summary

A 57-year-old woman with history of hypothyroidism and hypertension presented in May 2016 with a lump in her right breast and back pain. The lump was biopsied and revealed invasive ductal carcinoma, moderately differentiated, estrogen receptor (ER) positive 100%, progesterone receptor (PR) positive 95%, and HER2 negative. A positron emission tomography (PET)–computed tomography (CT) scan and magnetic resonance imaging showed bone metastasis at several vertebral levels, and the results of a bone biopsy confirmed metastatic adenocarcinoma of breast origin, ER positive 60%, PR positive 40%, and HER2 negative. No liver lesions were seen on imaging, but there was suggestion of fatty liver. She was started on letrozole 2.5 mg daily in July 2016 while undergoing kyphoplasty and subsequent radiation. A restaging PET scan revealed progression of disease on letrozole, with possible new rib lesion and progression in the breast. No liver disease was noted. Therapy was changed to fulvestrant and palbociclib. Fulvestrant was started in March 2017 with standard dosing of 500 mg intramuscular on days 1, 15, and 29, and then once a month thereafter. Her first cycle of palbociclib was started on April 5, dosed at 125 mg by mouth daily for 21 days, followed by 7 days off, repeated every 28 days (all dates hereinafter fell within 2017, unless otherwise stipulated).

Labs checked on April 28 and May 26 were unremarkable. A restaging CT scan of the chest, abdomen, and pelvis was done on June 21 after completion of 3 cycles of fulvestrant and palbociclib. There was no evidence of liver metastases, only the fatty infiltration of the liver that had been seen previously. On June 23, 2017, lab results showed a transaminitis with an alanine aminotransferase (ALT) level of 446 IU/L (reference range 10-33 IU/L) and aspartate aminotransferase (AST) level of 183 IU/L (reference range 0-32 IU/L).

The patient’s liver enzyme levels continued to increase and peaked on July 3 at ALT >700 IU/L and AST at 421 IU/L. Her total bilirubin and alkaline phosphatase levels remained within normal limits. She had received her final dose of fulvestrant on May 31 and had taken her last dose of palbociclib on June 20, 2017. She had no history of elevated liver enzymes or liver disease, although the initial PET scan done at diagnosis had suggested hepatic steatosis. She said she had not recently used antibiotics, alcohol, or over-the-counter medications or supplements. There was no family history of liver problems, inflammatory bowel disease, or gastrointestinal malignancy. The only other medications she had taken recently were denosumab, levothyroxine for hypothyroidism, and amlodipine for hypertension. She was seen by hepatology for evaluation of acute hepatitis. Other etiologies for her elevated liver enzymes were ruled out, and she was diagnosed with a drug-induced liver injury from one of her anticancer medications. Her treatments with fulvestrant and palbociclib were held, and the results of her liver function tests normalized by September 2017.

Fulvestrant was restarted on August 24, and her lab results remained normal through November of that year, when restaging scans showed progression with new axillary adenopathy suspicious for metastasis. Imaging also showed a 1.6-cm hepatic lesion suggestive of a focal area of fat deposition or atypical hemangioma without definitive evidence of metastasis. Follow-up imaging was recommended. She was therefore rechallenged with palbociclib at a reduced dose of 100 mg by mouth daily and received the first dose on November 30. On December 8, repeat labs again showed elevated liver function tests (ALT, 285 IU/L; AST, 112 IU/L). Treatment with palbociclib was discontinued on December 10. Because the patient was not able to tolerate palbociclib, and fulvestrant alone was not controlling the disease, she was started on an alternate endocrine therapy with tamoxifen on December 26. The patient’s liver function tests normalized again by January 2018.
 

Discussion

The use of targeted therapies has changed the landscape of oncologic treatments. Several studies have evaluated the safety and efficacy of palbociclib in combination with endocrine therapy. The Palbociclib Ongoing Trials in the Management of Breast Cancer (PALOMA)-1 study, an open-label, randomized, phase-2 trial involving patients with newly diagnosed metastatic hormone sensitive HER2-negative breast cancer, demonstrated that palbociclib in combination with letrozole was associated with significantly longer PFS than letrozole alone.⁴ These results were later confirmed in the larger PALOMA-2 study, a randomized, double-blind, phase-3 trial that evaluated 666 postmenopausal patients with no prior systemic therapy. In that study, median PFS for the palbociclib–letrozole group was 24.8 months, compared with 14.5 months for the letrozole-alone group (hazard ratio [HR] for disease progression or death, 0.58 [0.46–0.72], P < .001).⁵ The most recent PALOMA-3 study, a phase-3 trial involving 521 patients with advanced hormone receptor–positive, HER2-negative breast cancer that had progressed during initial endocrine therapy, evaluated the efficacy of combined palbociclib and fulvestrant in a randomized, double-blind, placebo-controlled, parallel-group trial. The result was that the palbociclib–fulvestrant combination resulted in longer median PFS of 9.2 months, compared with 3.8 months with fulvestrant alone (P < .001).⁶

These trials also monitored the number of AEs as secondary aims. The most commonly reported AEs in the PALOMA trials for those patients in the palbociclib group were hematologic, with neutropenia being the most common, followed by leukopenia, anemia, and thrombocytopenia. The most common nonhematologic AEs reported in the palbociclib-fulvestrant group were fatigue, nausea, and headache. Elevated liver function tests were a rare but reported AE in 7.2% of the palbociclib-treated patients in the PALOMA-1 study.⁷ In the PALOMA-2 study, ALT and AST elevations were reported as AEs (all grades) in 9.9% and 9.7% of palbociclib-treated patients, respectively.⁵ In the PALOMA-3 study, there was 1 fatal serious AE of hepatic failure with grade 5 disease progression in the palbociclib group; however, the patient’s medical history included progressive liver metastasis and disease progression.⁶ A pooled safety analysis conducted across all PALOMA studies demonstrated that grade 3/4 AST and ALT elevations occurred in 3.3% and 2.3% of palbociclib-treated patients, respectively, again highlighting a reported but rare occurrence.⁸

The patient described in the present case report started on combination fulvestrant and palbociclib after her disease showed progression on letrozole. She developed an increase in transaminases after completing 3 cycles of palbociclib. Liver function tests increased nearly 12 weeks after beginning her first cycle of the CDK 4/6 inhibitor. Staging scans of the patient demonstrated fatty liver. It is not known if her fatty liver contributed to her transminitis; however, her baseline labs showed normal liver function tests, and they did not increase until after therapy with fulvestrant–palbociclib was started. It might have been that her fatty liver caused her to be at higher risk of transaminitis with administration of palbociclib, although we cannot be certain. Her lab results remained normal while she was on fulvestrant alone, and the liver function test results increased only after palbociclib was started, making this drug the more likely culprit.

Both events of increased liver enzymes occurred within a week of the last palbociclib dose; however, we note that hepatotoxicity developed at a faster rate when the patient was rechallenged with palbociclib at a lower dose, with elevated liver function tests increasing 1 week after restarting treatment as opposed to the first episode that occurred after 3 cycles of the palbociclib. After discontinuation of the medication, liver function tests again normalized, suggesting that palbociclib was most likely the causative agent. In addition, the degree of elevated liver enzymes was less severe on re-exposure at the lower dose of 100 mg, which raises the possibility that there could be a dose-dependent association between palbociclib and hepatotoxicity. There have been few case reports of increased liver enzymes associated with palbociclib, and it is only recently that this association has been more recognized. A meta-analysis by Zaw and colleagues has demonstrated that CDK 4/6 inhibitor–based regimens are associated with a higher risk of elevated AST and ALT; however, their relation with dose dependence was not described. In particular, they found that CDK 4/6 inhibitors increased the risk of high-grade, elevated ALT with a relative risk of 4.33 (95% confidence interval, 2.15-8.71; P < .0001). The meta-analysis also included other CDK 4/6 inhibitors such as abemaciclib and ribociclib, which have been more commonly associated with liver toxicity than palbociclib has.⁹ Our case report highlights the specific association between palbociclib and elevated liver enzymes.

In conclusion, this case report illustrates that our patient’s elevated liver enzymes were likely related to palbociclib. This is further supported by the fact that this AE occurred twice, both times after palbociclib exposure. In each instance, liver enzymes normalized after discontinuation of palbociclib. One cannot entirely rule out that fulvestrant might have been the culprit medication, but the patient’s normal hepatic panel for several months after starting fulvestrant suggests that is less likely. This case report is indicative of an uncommon complication in the treatment of metastatic breast cancer, one that is starting to gain more recognition, and we must think of palbociclib as a possible cause of drug-induced liver injury when targeted CDK 4/6–based regimens are used.

About 12.4% of women in the United States will be diagnosed with breast cancer at some point in their lifetime.¹ A percentage of these women will develop metastatic disease and are estimated to have a 5-year survival rate of 22%.² There have been meaningful improvements in survival because of earlier detection and more effective systemic therapies. Patients with hormone-sensitive disease often respond to endocrine therapy, and this frequently represents front-line treatment for these patients, resulting in palliation of symptoms while maintaining quality of life.

However, endocrine resistance inevitably occurs, and a great deal of research has been focused on developing strategies to combat resistance. One mechanism of endocrine resistance is though the Cyclin-dependent kinases 4 and 6 (CDK4/6) complexes. Among the most promising of the strategies to prevent resistance are the CDK4/6 inhibitors. There are now 3 approved CDK4/6 inhibitor drugs that can be used in combination with endocrine therapy, 1 of which can also be used as a single agent. When used in combination with endocrine therapy, the use of CDK 4/6 inhibitors has significantly improved progression-free survival (PFS) in patients with hormone-sensitive HER2-negative metastatic breast cancer by inhibiting cellular division and growth.³ In postmenopausal women, endocrine therapy plus CDK4/6 inhibitors are the preferred first-line regimen for metastatic disease.

Since the approval of palbociclib by the US Food and Drug Administration in 2015, the most common hematologic lab abnormalities are anemia, leukopenia, neutropenia, and thrombocytopenia. The most common nonhematologic adverse events (AEs) are fatigue, infection, nausea, and stomatitis. Hepatic toxicity has not been commonly observed. We report here the case of a 57-year-old woman on palbociclib and fulvestrant who developed significant elevation of liver function tests after starting palbociclib, suggesting a possible drug-induced liver injury from palbociclib.
 

Case presentation and summary

A 57-year-old woman with history of hypothyroidism and hypertension presented in May 2016 with a lump in her right breast and back pain. The lump was biopsied and revealed invasive ductal carcinoma, moderately differentiated, estrogen receptor (ER) positive 100%, progesterone receptor (PR) positive 95%, and HER2 negative. A positron emission tomography (PET)–computed tomography (CT) scan and magnetic resonance imaging showed bone metastasis at several vertebral levels, and the results of a bone biopsy confirmed metastatic adenocarcinoma of breast origin, ER positive 60%, PR positive 40%, and HER2 negative. No liver lesions were seen on imaging, but there was suggestion of fatty liver. She was started on letrozole 2.5 mg daily in July 2016 while undergoing kyphoplasty and subsequent radiation. A restaging PET scan revealed progression of disease on letrozole, with possible new rib lesion and progression in the breast. No liver disease was noted. Therapy was changed to fulvestrant and palbociclib. Fulvestrant was started in March 2017 with standard dosing of 500 mg intramuscular on days 1, 15, and 29, and then once a month thereafter. Her first cycle of palbociclib was started on April 5, dosed at 125 mg by mouth daily for 21 days, followed by 7 days off, repeated every 28 days (all dates hereinafter fell within 2017, unless otherwise stipulated).

Labs checked on April 28 and May 26 were unremarkable. A restaging CT scan of the chest, abdomen, and pelvis was done on June 21 after completion of 3 cycles of fulvestrant and palbociclib. There was no evidence of liver metastases, only the fatty infiltration of the liver that had been seen previously. On June 23, 2017, lab results showed a transaminitis with an alanine aminotransferase (ALT) level of 446 IU/L (reference range 10-33 IU/L) and aspartate aminotransferase (AST) level of 183 IU/L (reference range 0-32 IU/L).

The patient’s liver enzyme levels continued to increase and peaked on July 3 at ALT >700 IU/L and AST at 421 IU/L. Her total bilirubin and alkaline phosphatase levels remained within normal limits. She had received her final dose of fulvestrant on May 31 and had taken her last dose of palbociclib on June 20, 2017. She had no history of elevated liver enzymes or liver disease, although the initial PET scan done at diagnosis had suggested hepatic steatosis. She said she had not recently used antibiotics, alcohol, or over-the-counter medications or supplements. There was no family history of liver problems, inflammatory bowel disease, or gastrointestinal malignancy. The only other medications she had taken recently were denosumab, levothyroxine for hypothyroidism, and amlodipine for hypertension. She was seen by hepatology for evaluation of acute hepatitis. Other etiologies for her elevated liver enzymes were ruled out, and she was diagnosed with a drug-induced liver injury from one of her anticancer medications. Her treatments with fulvestrant and palbociclib were held, and the results of her liver function tests normalized by September 2017.

Fulvestrant was restarted on August 24, and her lab results remained normal through November of that year, when restaging scans showed progression with new axillary adenopathy suspicious for metastasis. Imaging also showed a 1.6-cm hepatic lesion suggestive of a focal area of fat deposition or atypical hemangioma without definitive evidence of metastasis. Follow-up imaging was recommended. She was therefore rechallenged with palbociclib at a reduced dose of 100 mg by mouth daily and received the first dose on November 30. On December 8, repeat labs again showed elevated liver function tests (ALT, 285 IU/L; AST, 112 IU/L). Treatment with palbociclib was discontinued on December 10. Because the patient was not able to tolerate palbociclib, and fulvestrant alone was not controlling the disease, she was started on an alternate endocrine therapy with tamoxifen on December 26. The patient’s liver function tests normalized again by January 2018.
 

Discussion

The use of targeted therapies has changed the landscape of oncologic treatments. Several studies have evaluated the safety and efficacy of palbociclib in combination with endocrine therapy. The Palbociclib Ongoing Trials in the Management of Breast Cancer (PALOMA)-1 study, an open-label, randomized, phase-2 trial involving patients with newly diagnosed metastatic hormone sensitive HER2-negative breast cancer, demonstrated that palbociclib in combination with letrozole was associated with significantly longer PFS than letrozole alone.⁴ These results were later confirmed in the larger PALOMA-2 study, a randomized, double-blind, phase-3 trial that evaluated 666 postmenopausal patients with no prior systemic therapy. In that study, median PFS for the palbociclib–letrozole group was 24.8 months, compared with 14.5 months for the letrozole-alone group (hazard ratio [HR] for disease progression or death, 0.58 [0.46–0.72], P < .001).⁵ The most recent PALOMA-3 study, a phase-3 trial involving 521 patients with advanced hormone receptor–positive, HER2-negative breast cancer that had progressed during initial endocrine therapy, evaluated the efficacy of combined palbociclib and fulvestrant in a randomized, double-blind, placebo-controlled, parallel-group trial. The result was that the palbociclib–fulvestrant combination resulted in longer median PFS of 9.2 months, compared with 3.8 months with fulvestrant alone (P < .001).⁶

These trials also monitored the number of AEs as secondary aims. The most commonly reported AEs in the PALOMA trials for those patients in the palbociclib group were hematologic, with neutropenia being the most common, followed by leukopenia, anemia, and thrombocytopenia. The most common nonhematologic AEs reported in the palbociclib-fulvestrant group were fatigue, nausea, and headache. Elevated liver function tests were a rare but reported AE in 7.2% of the palbociclib-treated patients in the PALOMA-1 study.⁷ In the PALOMA-2 study, ALT and AST elevations were reported as AEs (all grades) in 9.9% and 9.7% of palbociclib-treated patients, respectively.⁵ In the PALOMA-3 study, there was 1 fatal serious AE of hepatic failure with grade 5 disease progression in the palbociclib group; however, the patient’s medical history included progressive liver metastasis and disease progression.⁶ A pooled safety analysis conducted across all PALOMA studies demonstrated that grade 3/4 AST and ALT elevations occurred in 3.3% and 2.3% of palbociclib-treated patients, respectively, again highlighting a reported but rare occurrence.⁸

The patient described in the present case report started on combination fulvestrant and palbociclib after her disease showed progression on letrozole. She developed an increase in transaminases after completing 3 cycles of palbociclib. Liver function tests increased nearly 12 weeks after beginning her first cycle of the CDK 4/6 inhibitor. Staging scans of the patient demonstrated fatty liver. It is not known if her fatty liver contributed to her transminitis; however, her baseline labs showed normal liver function tests, and they did not increase until after therapy with fulvestrant–palbociclib was started. It might have been that her fatty liver caused her to be at higher risk of transaminitis with administration of palbociclib, although we cannot be certain. Her lab results remained normal while she was on fulvestrant alone, and the liver function test results increased only after palbociclib was started, making this drug the more likely culprit.

Both events of increased liver enzymes occurred within a week of the last palbociclib dose; however, we note that hepatotoxicity developed at a faster rate when the patient was rechallenged with palbociclib at a lower dose, with elevated liver function tests increasing 1 week after restarting treatment as opposed to the first episode that occurred after 3 cycles of the palbociclib. After discontinuation of the medication, liver function tests again normalized, suggesting that palbociclib was most likely the causative agent. In addition, the degree of elevated liver enzymes was less severe on re-exposure at the lower dose of 100 mg, which raises the possibility that there could be a dose-dependent association between palbociclib and hepatotoxicity. There have been few case reports of increased liver enzymes associated with palbociclib, and it is only recently that this association has been more recognized. A meta-analysis by Zaw and colleagues has demonstrated that CDK 4/6 inhibitor–based regimens are associated with a higher risk of elevated AST and ALT; however, their relation with dose dependence was not described. In particular, they found that CDK 4/6 inhibitors increased the risk of high-grade, elevated ALT with a relative risk of 4.33 (95% confidence interval, 2.15-8.71; P < .0001). The meta-analysis also included other CDK 4/6 inhibitors such as abemaciclib and ribociclib, which have been more commonly associated with liver toxicity than palbociclib has.⁹ Our case report highlights the specific association between palbociclib and elevated liver enzymes.

In conclusion, this case report illustrates that our patient’s elevated liver enzymes were likely related to palbociclib. This is further supported by the fact that this AE occurred twice, both times after palbociclib exposure. In each instance, liver enzymes normalized after discontinuation of palbociclib. One cannot entirely rule out that fulvestrant might have been the culprit medication, but the patient’s normal hepatic panel for several months after starting fulvestrant suggests that is less likely. This case report is indicative of an uncommon complication in the treatment of metastatic breast cancer, one that is starting to gain more recognition, and we must think of palbociclib as a possible cause of drug-induced liver injury when targeted CDK 4/6–based regimens are used.

Anemia is a common complication of cancer treatment as well as of cancer itself. Most cancer patients undergoing chemotherapy experience anemia sometime during their treatment course.^1,2 Moderate to severe anemia is associated with an array of symptoms that are known to compromise the physical functioning and quality of life of cancer patients. Common anemia-related symptoms include fatigue, drowsiness, depression, dyspnea, tachycardia, and dizziness.^1,3-7

Symptoms produced by cancer itself or the disease treatment (ie, side effects such as anemia) collectively compose a patient’s symptom burden.⁸ Although the occurrence of anemia-related fatigue has been described more systematically, other clinical presentations of chemotherapy-induced anemia (CIA) are not well characterized. Furthermore, the overall symptom burdens associated with different ranges of hemoglobin (Hb) concentrations have also not been well reported. Although various tools have been developed to facilitate the reporting of fatigue and other symptoms experienced by patients with CIA, such as the Functional Assessment of Cancer Therapy-Anemia (FACT-An) questionnaire and the MD Anderson Symptom Inventory (MDASI),^9-11 these questionnaires have not been extensively used outside of the research context. As such, knowledge on symptom burdens associated with CIA in real-world patient populations remains lacking.

Given the common occurrence of CIA, management of CIA and associated symptoms plays an important role to patients’ quality of life during cancer treatment. Symptom control is often the main goal for patients with stage IV cancers, as treatment for disease is most likely palliative or noncurative. To facilitate supportive care planning, it is important to understand patient symptom burdens as chemotherapy progresses over cycles and Hb levels decline. We conducted a comprehensive medical record review study in patients diagnosed with stage IV non-Hodgkin lymphoma (NHL), breast cancer, and lung cancers at Kaiser Permanente Southern California (KPSC), a large community-based health care delivery system. The objective of this study was to report the occurrence of CIA-related symptoms throughout the course of chemotherapy and by Hb levels.
 

Methods

Study setting and population

KPSC is an integrated managed-care organization that provides comprehensive health services for 4 million racially, ethnically, and socioeconomically diverse members who broadly represent the population in Southern California.¹² The organization maintains electronic records of health care received by its members, including physician record notes and clinical databases such as laboratory test results, diagnosis codes, medical procedures, medication dispenses, and disease registries. KPSC’s cancer registry is Surveillance, Epidemiology, and End Results, which is affiliated and routinely collects information on age, sex, race and/or ethnicity, cancer type, histology, and stage at diagnosis.

Patients who met the following inclusion criteria were included in this study: diagnosed with stage IV NHL, breast cancer, or lung cancer at age 18 years or older at KPSC between March 25, 2010 and December 31, 2012; initiated myelosuppressive chemotherapy at KPSC before June 30, 2013 (only the first chemotherapy course was included in this evaluation); and had at least 1 Hb measurement during the course of chemotherapy. Of those who met the inclusion criteria, patients who met the following criteria were excluded if they had less than 12 months KPSC membership before start of chemotherapy, missing information on cancer stage or chemotherapy regimen/agents, a diagnosis of myelodysplastic syndrome before chemotherapy initiation, a diagnosis of inherited anemia, an Hb concentration <10 g/L within 3 months before chemotherapy initiation, a transfusion within 2 weeks before chemotherapy initiation, radiation within 4 months before chemotherapy initiation, or bone marrow transplantation within 12 months before chemotherapy initiation or during the chemotherapy course. These exclusion criteria were applied to evaluate symptom burdens most likely related to CIA as opposed to other cancer treatment or pre-existing anemia.

CIA in this study was defined as moderate to severe anemia with Hb <10 g/dL after chemotherapy initiation. Based on this definition for CIA, all patients who developed CIA between the first chemotherapy administration to 60 days after the last dose of chemotherapy were included for the record review. In addition, a random sample of 100 patients who did not develop CIA (ie, did not reach an Hb <10 g/dL during chemotherapy) but otherwise met study eligibility criteria was also reviewed to serve as a comparison group. Of those, 2 patients were subsequently excluded after record review because of findings of ineligibility, so only 98 patients were presented. The large number of patients (ie, >4,000) who did not develop CIA made record review of all patients infeasible.
 

Data collection

Data on anemia-related symptoms or signs and anemia-related comorbidities (Table 1) were collected by standardized review of physician record notes in the electronic medical records. A set of 24 anemia-related symptoms were identified based on the literature and clinical expertise and included abdominal pain, blurred vision/double vision/loss of vision, cold intolerance/coldness in hands or feet, depression/anxiety, diarrhea, dizziness/lightheadedness, dyspnea/shortness of breath/tachypnea, edema, fatigue, headache, heart failure, heat intolerance, hypotension, insomnia, leg pain, loss of appetite, nausea/vomiting, pale skin, palpitations/tachycardia, paralysis/ataxia/numbness or tingling in extremities, pectoral angina/chest pain, sweating/diaphoresis, syncope, and vertigo. Record review period was defined as 1 month before chemotherapy to 60 days after the last dose of chemotherapy in the first course. To understand the development of new symptoms during chemotherapy treatment, pre-existing symptoms documented within 1 month before chemotherapy initiation were recorded. The entire record review process was standardized between 2 trained abstractors, including the training, instruction manual, ongoing feedback, abstraction form/database, and coding.

The data elements extracted included the date the symptom was documented, date the symptom started, symptom duration (when available), and any relevant comments regarding the symptom (ie, if dyspnea was at rest or on exertion, whether the symptom was a side effect caused by chemotherapy, or change in symptom severity). Ten percent of the records were reviewed independently by 2 abstractors to ensure quality control. Additional quality control measures included SAS algorithms (SAS Institute, Inc., Cary, North Carolina) to check reasonability and logical consistency in the abstracted data.

Patient demographic characteristics, cancer stage, additional selected comorbidities (Table 1), chemotherapy information, Hb test results, and anemia treatment, including erythrocyte stimulating agent (ESA) use and red blood cell transfusion, were collected using KPSC’s cancer registry and clinical databases. Anemia was defined by severity as grade 1 (10 g/dL to lower limit of normal, ie, 14 g/dL for men and 12 g/dL for women), grade 2 (8.0-9.9 g/dL), grade 3 (6.5-7.9 g/dL), and grade 4 (<6.5 g/dL) following the National Cancer Institute’s Common Terminology Criteria for Adverse Events.¹³

Statistical analysis

Distributions of demographic, cancer, and treatment characteristics were calculated by CIA status, overall and by cancer type. Differences between patients who did and did not develop CIA were assessed using chi-square test and Kruskal-Wallis test. For those who developed CIA, the distribution of the worst anemia grade was also calculated for each cycle of chemotherapy.

Next, the distributions for the following symptom categories were calculated in the 2 study samples defined by CIA status: pre-existing symptoms that occurred before chemotherapy, any symptoms during chemotherapy (ie, whether they started before chemotherapy), and incident symptoms during chemotherapy (ie, new symptoms that only started after chemotherapy). Specifically, the proportion of patients with each individual symptom and the distribution of the number of symptoms per patient were calculated. Differences in symptom distribution by CIA status were assessed using chi-square test.

The distribution of symptoms in each chemotherapy cycle was calculated up to 6 chemotherapy cycles (as >80% of the patients only had treatment up to 6 cycles) in the 2 study samples defined by CIA status. For this analysis, a symptom was “mapped” to a cycle if the date (or date range) of the symptom fell within the date range of that chemotherapy cycle. In patients who developed CIA, the distribution of symptoms was also calculated by anemia grade. This was again done on the chemotherapy cycle level. For each chemotherapy cycle, an anemia grade was assigned (no anemia or anemia grade 1, 2, 3, and 4) using the lowest Hb measurement in that cycle. Symptoms that occurred in a chemotherapy cycle were then “mapped” to the anemia grade of that cycle. Some patients had more than 1 anemia event of the same grade (eg, if a patient’s grade 2 anemia persist across cycles). For these patients, we randomly selected only 1 anemia event of the same grade from each patient to be included in this analysis. Patients could still contribute multiple events of different grades to this analysis. We calculated the mean number of symptoms per patient for each anemia grade (ie, 1-4) separately. Because of the small number of patients who developed grade 4 anemia (n = 11), they were combined with the grade 3 patients when the distributions of individual symptoms were evaluated.

All analyses were repeated stratified by gender. P values for differences between men and women were calculated using chi-square test or t test. All analyses were conducted using SAS version 9.3.
 

Results

A total of 402 stage IV NHL, breast, and lung cancer patients who developed CIA and 98 patients who did not develop CIA during the first course of chemotherapy were included (Figure 1).

Table 3 shows the number and proportion of study patients with each of the symptoms documented before and after chemotherapy initiation for the 2 study samples. Patients who developed CIA had statistically significantly more pre-existing symptoms, incident symptoms, or any symptoms that occurred during chemotherapy compared with patients who did not develop CIA. The mean number of pre-existing symptoms was 1.7 (standard deviation [SD], 2.0) for those with CIA and 1.2 (SD, 1.5) for those without CIA (P = .04). The mean number of symptoms that occurred during chemotherapy was 6.8 (SD, 3.4) and 4.1 (SD, 2.7), respectively (P < .01). Of individual symptoms, fatigue was the most commonly documented symptom during chemotherapy in patients who developed CIA, noted in 90% of the study sample (Table 3). Dyspnea/shortness of breath (58%), nausea/vomiting (56%), and loss of appetite (56%) were documented in 50% or more of these patients. Abdominal pain (35%), depression/anxiety (43%), dizziness/lightheadedness (30%), edema (39%), palpitations/tachycardia (34%), and pectoral angina/chest pain (34%) were documented in 30% or more of these patients. In patients who did not develop CIA, fatigue remained the most prevalent symptom (77% of the patients). Other than fatigue, only dyspnea/shortness of breath (41%), nausea/vomiting (43%) and paralysis/ataxia/tingling in extremities (33%) were noted in 30% or more of this study sample.

Discussion

In this study, we described the number and type of symptoms documented in the medical record notes among stage IV NHL, breast cancer, and lung cancer patients who did or did not develop CIA during chemotherapy. Patients who developed CIA had significantly greater numbers of different symptoms documented during chemotherapy than those who did not develop CIA (6.8 vs 4.1). This difference is clinically significant because most symptoms described in this study can be expected to have a negative impact on a patient’s quality of life. In patients who developed CIA, fatigue was the most commonly documented symptom, noted for 90% of the study population. In addition to fatigue, many other symptoms were noted in a large proportion of patients. In contrast, in patients who did not develop CIA, only a few symptoms (including fatigue) were more commonly noted in this sample. We observed more symptoms in chemotherapy cycles with higher grades of anemia. Of the symptoms examined, abdominal pain, depression, diarrhea, dizziness/lightheadedness, dyspnea, edema, fatigue, heart failure, headache, hypotension, insomnia, leg pain, loss of appetite, nausea/vomiting, pale skin, pectoral angina, sweating, and syncope particularly demonstrated a clearly increasing prevalence with declining Hb level. We also reported that patients who developed severe anemia (grades 3 and 4) experienced an average of 5 to 6 different symptoms at the time of the anemia episode. These data demonstrated a significant symptom burden in cancer patients with CIA seen in community-based oncology practices. Findings on the types of symptoms most commonly noted in various grades of CIA episodes provided some guidance for supportive care planning. As previous studies have shown a reduction in symptom burden after anemia treatment in patients with CIA,^14-16 our results support the idea of early lab draws and active management of CIA in maintaining quality of life in cancer patients undergoing chemotherapy.

Our findings on the prevalence of fatigue are in line with other studies in the literature. Maxwell reported that the prevalence of fatigue was 80% to 96% in cancer patients.¹⁷ Cella and colleagues found that using FACT-General questionnaire, 75% of cancer patients reported fatigue.¹¹ The comparability of our estimate and those found in studies based on patient self-report offered some assurance of the validity of assessing symptom prevalence through physician record notes. In addition to fatigue, we described prevalence of 23 additional symptoms, most of which have not been extensively studied in the literature. Gabrilove and colleagues found that a substantial proportion of patients with CIA had moderate to severe score for lack of appetite (36%) and disturbed sleep (41%) using the MDASI.¹⁰ The prevalence of loss of appetite and insomnia was around 50% and 25%, respectively, in our study samples. A 2013 systematic review of 21 multinational studies reported the pooled prevalence of several nonfatigue symptoms in cancer patients including headache (23%), sleep disturbance/insomnia (49%), appetite changes (45%), nausea/vomiting (26%), diarrhea (15%), depression (34%), dyspnea (44%), dizziness (26%), numbness/tingling (42%), edema (14%), and sweating (28%).¹⁸ Our prevalence estimates in patients with CIA for most of these symptoms were higher, likely because Reilly and colleagues used source studies that included any cancer patients undergoing treatment and not just those with CIA. Our findings on the increased symptom burden in patients who experienced episodes of advanced anemia compared with patients with mild anemia were also consistent with the literature. To this end, several studies using MDASI or the FACT-An reported differential symptom burdens by Hb level based on patient self-report,^10,11,19 including data on improvement in symptom burden and quality of life after anemia was amended with the use of ESA.^20,21

We found that the number of pre-existing symptoms was significantly higher in patients who went on to develop CIA than in patients who did not develop CIA. Specifically, fatigue, loss of appetite, and pale skin before chemotherapy seemed to be significantly more common in patients who went on to develop CIA. This finding suggested that presentation of these symptoms before chemotherapy initiation may be a predictor for developing moderate or severe anemia during treatment. This is a novel hypothesis, as no studies have evaluated the relationship between pretreatment symptom and risk of CIA. However, our study was not designed to address this specific question. Additional investigation is needed to further shed light on whether the occurrence of anemia-related symptoms in nonanemic patients can be used to effectively risk-stratify patients for subsequent CIA.

Contrary to our expectation, the prevalence of most symptoms did not clearly increase as chemotherapy progressed. There are several possible explanations to this phenomenon, with the most likely being related to reporting of anemia-related symptoms. For example, patients might stop reporting the same symptom repeatedly or become adjusted to the new Hb levels, leading to less symptom manifestation. Clinicians may also be less likely to ask about symptoms in later treatment cycles and/or to document chronic symptoms. Several symptoms were rarely documented altogether, such as cold intolerance, heat intolerance, heart failure, and vertigo. Symptoms reported in earlier cycles could also be managed successfully. Another possible explanation is differential loss of follow-up. Patients who experienced severe adverse events or symptoms may terminate treatment prematurely. Thus, symptom burden found toward later cycles may not represent the true symptom burden should everyone who initiated the chemotherapy treatment complete all planned cycles.
 

Limitations

In addition to the limitations already discussed, there are several others that should be considered when interpreting our results. We did not have a consistent measure of symptom severity in the medical records. Duration of symptoms was also often poorly documented by physicians. Therefore, our results are not directly comparable with studies such as the MDASI that incorporate severity or duration in their prevalence measure. There may also be “reporting bias” by the clinicians owing to different perceived levels of severity or clinical relevance of the different symptoms. As a result, some symptoms may be underdocumented, leading to undercounting.

We also did not distinguish the exact cause of the symptoms (ie, owing to anemia, cancer, chemotherapy itself, or other chemotherapy-induced complications), as it was not possible to reliably ascertain the cause from record review. Furthermore, symptom assessment was not separately performed for grade 4 anemia because of the small number of events in the study population. We also did not plan to evaluate the impact of anemia treatment on symptom burden, as our goal was to comprehensively describe a wide spectrum of symptoms experienced by patients with different Hb levels. However, previous studies have shown the benefit of treatments that correct CIA in symptom management.^14-16 Finally, this study does not inform about the relative importance of these symptoms to patients’ quality of life. To this end, a qualitative study found fatigue, shortness of breath, and lightheadedness/dizziness to be the most important symptoms ranked by patients with CIA.²²

Despite the potential limitations, our study has several important strengths. In addition to fatigue, patients with CIA suffer from a wide range of other anemia-related symptoms, but data on the prevalence of these symptoms have been lacking. To our knowledge, this is among the first studies that collected data on a comprehensive list of symptoms and provided detailed analysis by chemotherapy cycle and anemia grade. The combined use of KPSC’s clinical databases and medical record review allowed us to provide detailed characterization of the study population in terms of their treatment history, history of comorbidities, and laboratory data.
 

Conclusions

Our data provide physicians a comprehensive picture of prevalence of various types of symptoms and how symptom burden evolves as chemotherapy cycle and anemia severity progress. High-grade CIA correlates with an increased symptom burden. Such an understanding can be crucial in facilitating supportive care planning by helping physicians anticipate the timing and proactively determine the management approach of chemotherapy-related anemia and its symptoms.

Anemia is a common complication of cancer treatment as well as of cancer itself. Most cancer patients undergoing chemotherapy experience anemia sometime during their treatment course.^1,2 Moderate to severe anemia is associated with an array of symptoms that are known to compromise the physical functioning and quality of life of cancer patients. Common anemia-related symptoms include fatigue, drowsiness, depression, dyspnea, tachycardia, and dizziness.^1,3-7

Symptoms produced by cancer itself or the disease treatment (ie, side effects such as anemia) collectively compose a patient’s symptom burden.⁸ Although the occurrence of anemia-related fatigue has been described more systematically, other clinical presentations of chemotherapy-induced anemia (CIA) are not well characterized. Furthermore, the overall symptom burdens associated with different ranges of hemoglobin (Hb) concentrations have also not been well reported. Although various tools have been developed to facilitate the reporting of fatigue and other symptoms experienced by patients with CIA, such as the Functional Assessment of Cancer Therapy-Anemia (FACT-An) questionnaire and the MD Anderson Symptom Inventory (MDASI),^9-11 these questionnaires have not been extensively used outside of the research context. As such, knowledge on symptom burdens associated with CIA in real-world patient populations remains lacking.

Given the common occurrence of CIA, management of CIA and associated symptoms plays an important role to patients’ quality of life during cancer treatment. Symptom control is often the main goal for patients with stage IV cancers, as treatment for disease is most likely palliative or noncurative. To facilitate supportive care planning, it is important to understand patient symptom burdens as chemotherapy progresses over cycles and Hb levels decline. We conducted a comprehensive medical record review study in patients diagnosed with stage IV non-Hodgkin lymphoma (NHL), breast cancer, and lung cancers at Kaiser Permanente Southern California (KPSC), a large community-based health care delivery system. The objective of this study was to report the occurrence of CIA-related symptoms throughout the course of chemotherapy and by Hb levels.
 

Methods

Study setting and population

KPSC is an integrated managed-care organization that provides comprehensive health services for 4 million racially, ethnically, and socioeconomically diverse members who broadly represent the population in Southern California.¹² The organization maintains electronic records of health care received by its members, including physician record notes and clinical databases such as laboratory test results, diagnosis codes, medical procedures, medication dispenses, and disease registries. KPSC’s cancer registry is Surveillance, Epidemiology, and End Results, which is affiliated and routinely collects information on age, sex, race and/or ethnicity, cancer type, histology, and stage at diagnosis.

Patients who met the following inclusion criteria were included in this study: diagnosed with stage IV NHL, breast cancer, or lung cancer at age 18 years or older at KPSC between March 25, 2010 and December 31, 2012; initiated myelosuppressive chemotherapy at KPSC before June 30, 2013 (only the first chemotherapy course was included in this evaluation); and had at least 1 Hb measurement during the course of chemotherapy. Of those who met the inclusion criteria, patients who met the following criteria were excluded if they had less than 12 months KPSC membership before start of chemotherapy, missing information on cancer stage or chemotherapy regimen/agents, a diagnosis of myelodysplastic syndrome before chemotherapy initiation, a diagnosis of inherited anemia, an Hb concentration <10 g/L within 3 months before chemotherapy initiation, a transfusion within 2 weeks before chemotherapy initiation, radiation within 4 months before chemotherapy initiation, or bone marrow transplantation within 12 months before chemotherapy initiation or during the chemotherapy course. These exclusion criteria were applied to evaluate symptom burdens most likely related to CIA as opposed to other cancer treatment or pre-existing anemia.

CIA in this study was defined as moderate to severe anemia with Hb <10 g/dL after chemotherapy initiation. Based on this definition for CIA, all patients who developed CIA between the first chemotherapy administration to 60 days after the last dose of chemotherapy were included for the record review. In addition, a random sample of 100 patients who did not develop CIA (ie, did not reach an Hb <10 g/dL during chemotherapy) but otherwise met study eligibility criteria was also reviewed to serve as a comparison group. Of those, 2 patients were subsequently excluded after record review because of findings of ineligibility, so only 98 patients were presented. The large number of patients (ie, >4,000) who did not develop CIA made record review of all patients infeasible.
 

Data collection

Data on anemia-related symptoms or signs and anemia-related comorbidities (Table 1) were collected by standardized review of physician record notes in the electronic medical records. A set of 24 anemia-related symptoms were identified based on the literature and clinical expertise and included abdominal pain, blurred vision/double vision/loss of vision, cold intolerance/coldness in hands or feet, depression/anxiety, diarrhea, dizziness/lightheadedness, dyspnea/shortness of breath/tachypnea, edema, fatigue, headache, heart failure, heat intolerance, hypotension, insomnia, leg pain, loss of appetite, nausea/vomiting, pale skin, palpitations/tachycardia, paralysis/ataxia/numbness or tingling in extremities, pectoral angina/chest pain, sweating/diaphoresis, syncope, and vertigo. Record review period was defined as 1 month before chemotherapy to 60 days after the last dose of chemotherapy in the first course. To understand the development of new symptoms during chemotherapy treatment, pre-existing symptoms documented within 1 month before chemotherapy initiation were recorded. The entire record review process was standardized between 2 trained abstractors, including the training, instruction manual, ongoing feedback, abstraction form/database, and coding.

The data elements extracted included the date the symptom was documented, date the symptom started, symptom duration (when available), and any relevant comments regarding the symptom (ie, if dyspnea was at rest or on exertion, whether the symptom was a side effect caused by chemotherapy, or change in symptom severity). Ten percent of the records were reviewed independently by 2 abstractors to ensure quality control. Additional quality control measures included SAS algorithms (SAS Institute, Inc., Cary, North Carolina) to check reasonability and logical consistency in the abstracted data.

Patient demographic characteristics, cancer stage, additional selected comorbidities (Table 1), chemotherapy information, Hb test results, and anemia treatment, including erythrocyte stimulating agent (ESA) use and red blood cell transfusion, were collected using KPSC’s cancer registry and clinical databases. Anemia was defined by severity as grade 1 (10 g/dL to lower limit of normal, ie, 14 g/dL for men and 12 g/dL for women), grade 2 (8.0-9.9 g/dL), grade 3 (6.5-7.9 g/dL), and grade 4 (<6.5 g/dL) following the National Cancer Institute’s Common Terminology Criteria for Adverse Events.¹³

Statistical analysis

Distributions of demographic, cancer, and treatment characteristics were calculated by CIA status, overall and by cancer type. Differences between patients who did and did not develop CIA were assessed using chi-square test and Kruskal-Wallis test. For those who developed CIA, the distribution of the worst anemia grade was also calculated for each cycle of chemotherapy.

Next, the distributions for the following symptom categories were calculated in the 2 study samples defined by CIA status: pre-existing symptoms that occurred before chemotherapy, any symptoms during chemotherapy (ie, whether they started before chemotherapy), and incident symptoms during chemotherapy (ie, new symptoms that only started after chemotherapy). Specifically, the proportion of patients with each individual symptom and the distribution of the number of symptoms per patient were calculated. Differences in symptom distribution by CIA status were assessed using chi-square test.

The distribution of symptoms in each chemotherapy cycle was calculated up to 6 chemotherapy cycles (as >80% of the patients only had treatment up to 6 cycles) in the 2 study samples defined by CIA status. For this analysis, a symptom was “mapped” to a cycle if the date (or date range) of the symptom fell within the date range of that chemotherapy cycle. In patients who developed CIA, the distribution of symptoms was also calculated by anemia grade. This was again done on the chemotherapy cycle level. For each chemotherapy cycle, an anemia grade was assigned (no anemia or anemia grade 1, 2, 3, and 4) using the lowest Hb measurement in that cycle. Symptoms that occurred in a chemotherapy cycle were then “mapped” to the anemia grade of that cycle. Some patients had more than 1 anemia event of the same grade (eg, if a patient’s grade 2 anemia persist across cycles). For these patients, we randomly selected only 1 anemia event of the same grade from each patient to be included in this analysis. Patients could still contribute multiple events of different grades to this analysis. We calculated the mean number of symptoms per patient for each anemia grade (ie, 1-4) separately. Because of the small number of patients who developed grade 4 anemia (n = 11), they were combined with the grade 3 patients when the distributions of individual symptoms were evaluated.

All analyses were repeated stratified by gender. P values for differences between men and women were calculated using chi-square test or t test. All analyses were conducted using SAS version 9.3.
 

Results

A total of 402 stage IV NHL, breast, and lung cancer patients who developed CIA and 98 patients who did not develop CIA during the first course of chemotherapy were included (Figure 1).

Table 3 shows the number and proportion of study patients with each of the symptoms documented before and after chemotherapy initiation for the 2 study samples. Patients who developed CIA had statistically significantly more pre-existing symptoms, incident symptoms, or any symptoms that occurred during chemotherapy compared with patients who did not develop CIA. The mean number of pre-existing symptoms was 1.7 (standard deviation [SD], 2.0) for those with CIA and 1.2 (SD, 1.5) for those without CIA (P = .04). The mean number of symptoms that occurred during chemotherapy was 6.8 (SD, 3.4) and 4.1 (SD, 2.7), respectively (P < .01). Of individual symptoms, fatigue was the most commonly documented symptom during chemotherapy in patients who developed CIA, noted in 90% of the study sample (Table 3). Dyspnea/shortness of breath (58%), nausea/vomiting (56%), and loss of appetite (56%) were documented in 50% or more of these patients. Abdominal pain (35%), depression/anxiety (43%), dizziness/lightheadedness (30%), edema (39%), palpitations/tachycardia (34%), and pectoral angina/chest pain (34%) were documented in 30% or more of these patients. In patients who did not develop CIA, fatigue remained the most prevalent symptom (77% of the patients). Other than fatigue, only dyspnea/shortness of breath (41%), nausea/vomiting (43%) and paralysis/ataxia/tingling in extremities (33%) were noted in 30% or more of this study sample.

Discussion

In this study, we described the number and type of symptoms documented in the medical record notes among stage IV NHL, breast cancer, and lung cancer patients who did or did not develop CIA during chemotherapy. Patients who developed CIA had significantly greater numbers of different symptoms documented during chemotherapy than those who did not develop CIA (6.8 vs 4.1). This difference is clinically significant because most symptoms described in this study can be expected to have a negative impact on a patient’s quality of life. In patients who developed CIA, fatigue was the most commonly documented symptom, noted for 90% of the study population. In addition to fatigue, many other symptoms were noted in a large proportion of patients. In contrast, in patients who did not develop CIA, only a few symptoms (including fatigue) were more commonly noted in this sample. We observed more symptoms in chemotherapy cycles with higher grades of anemia. Of the symptoms examined, abdominal pain, depression, diarrhea, dizziness/lightheadedness, dyspnea, edema, fatigue, heart failure, headache, hypotension, insomnia, leg pain, loss of appetite, nausea/vomiting, pale skin, pectoral angina, sweating, and syncope particularly demonstrated a clearly increasing prevalence with declining Hb level. We also reported that patients who developed severe anemia (grades 3 and 4) experienced an average of 5 to 6 different symptoms at the time of the anemia episode. These data demonstrated a significant symptom burden in cancer patients with CIA seen in community-based oncology practices. Findings on the types of symptoms most commonly noted in various grades of CIA episodes provided some guidance for supportive care planning. As previous studies have shown a reduction in symptom burden after anemia treatment in patients with CIA,^14-16 our results support the idea of early lab draws and active management of CIA in maintaining quality of life in cancer patients undergoing chemotherapy.

Our findings on the prevalence of fatigue are in line with other studies in the literature. Maxwell reported that the prevalence of fatigue was 80% to 96% in cancer patients.¹⁷ Cella and colleagues found that using FACT-General questionnaire, 75% of cancer patients reported fatigue.¹¹ The comparability of our estimate and those found in studies based on patient self-report offered some assurance of the validity of assessing symptom prevalence through physician record notes. In addition to fatigue, we described prevalence of 23 additional symptoms, most of which have not been extensively studied in the literature. Gabrilove and colleagues found that a substantial proportion of patients with CIA had moderate to severe score for lack of appetite (36%) and disturbed sleep (41%) using the MDASI.¹⁰ The prevalence of loss of appetite and insomnia was around 50% and 25%, respectively, in our study samples. A 2013 systematic review of 21 multinational studies reported the pooled prevalence of several nonfatigue symptoms in cancer patients including headache (23%), sleep disturbance/insomnia (49%), appetite changes (45%), nausea/vomiting (26%), diarrhea (15%), depression (34%), dyspnea (44%), dizziness (26%), numbness/tingling (42%), edema (14%), and sweating (28%).¹⁸ Our prevalence estimates in patients with CIA for most of these symptoms were higher, likely because Reilly and colleagues used source studies that included any cancer patients undergoing treatment and not just those with CIA. Our findings on the increased symptom burden in patients who experienced episodes of advanced anemia compared with patients with mild anemia were also consistent with the literature. To this end, several studies using MDASI or the FACT-An reported differential symptom burdens by Hb level based on patient self-report,^10,11,19 including data on improvement in symptom burden and quality of life after anemia was amended with the use of ESA.^20,21

We found that the number of pre-existing symptoms was significantly higher in patients who went on to develop CIA than in patients who did not develop CIA. Specifically, fatigue, loss of appetite, and pale skin before chemotherapy seemed to be significantly more common in patients who went on to develop CIA. This finding suggested that presentation of these symptoms before chemotherapy initiation may be a predictor for developing moderate or severe anemia during treatment. This is a novel hypothesis, as no studies have evaluated the relationship between pretreatment symptom and risk of CIA. However, our study was not designed to address this specific question. Additional investigation is needed to further shed light on whether the occurrence of anemia-related symptoms in nonanemic patients can be used to effectively risk-stratify patients for subsequent CIA.

Contrary to our expectation, the prevalence of most symptoms did not clearly increase as chemotherapy progressed. There are several possible explanations to this phenomenon, with the most likely being related to reporting of anemia-related symptoms. For example, patients might stop reporting the same symptom repeatedly or become adjusted to the new Hb levels, leading to less symptom manifestation. Clinicians may also be less likely to ask about symptoms in later treatment cycles and/or to document chronic symptoms. Several symptoms were rarely documented altogether, such as cold intolerance, heat intolerance, heart failure, and vertigo. Symptoms reported in earlier cycles could also be managed successfully. Another possible explanation is differential loss of follow-up. Patients who experienced severe adverse events or symptoms may terminate treatment prematurely. Thus, symptom burden found toward later cycles may not represent the true symptom burden should everyone who initiated the chemotherapy treatment complete all planned cycles.
 

Limitations

In addition to the limitations already discussed, there are several others that should be considered when interpreting our results. We did not have a consistent measure of symptom severity in the medical records. Duration of symptoms was also often poorly documented by physicians. Therefore, our results are not directly comparable with studies such as the MDASI that incorporate severity or duration in their prevalence measure. There may also be “reporting bias” by the clinicians owing to different perceived levels of severity or clinical relevance of the different symptoms. As a result, some symptoms may be underdocumented, leading to undercounting.

We also did not distinguish the exact cause of the symptoms (ie, owing to anemia, cancer, chemotherapy itself, or other chemotherapy-induced complications), as it was not possible to reliably ascertain the cause from record review. Furthermore, symptom assessment was not separately performed for grade 4 anemia because of the small number of events in the study population. We also did not plan to evaluate the impact of anemia treatment on symptom burden, as our goal was to comprehensively describe a wide spectrum of symptoms experienced by patients with different Hb levels. However, previous studies have shown the benefit of treatments that correct CIA in symptom management.^14-16 Finally, this study does not inform about the relative importance of these symptoms to patients’ quality of life. To this end, a qualitative study found fatigue, shortness of breath, and lightheadedness/dizziness to be the most important symptoms ranked by patients with CIA.²²

Despite the potential limitations, our study has several important strengths. In addition to fatigue, patients with CIA suffer from a wide range of other anemia-related symptoms, but data on the prevalence of these symptoms have been lacking. To our knowledge, this is among the first studies that collected data on a comprehensive list of symptoms and provided detailed analysis by chemotherapy cycle and anemia grade. The combined use of KPSC’s clinical databases and medical record review allowed us to provide detailed characterization of the study population in terms of their treatment history, history of comorbidities, and laboratory data.
 

Conclusions

Our data provide physicians a comprehensive picture of prevalence of various types of symptoms and how symptom burden evolves as chemotherapy cycle and anemia severity progress. High-grade CIA correlates with an increased symptom burden. Such an understanding can be crucial in facilitating supportive care planning by helping physicians anticipate the timing and proactively determine the management approach of chemotherapy-related anemia and its symptoms.

Anemia is a common complication of cancer treatment as well as of cancer itself. Most cancer patients undergoing chemotherapy experience anemia sometime during their treatment course.^1,2 Moderate to severe anemia is associated with an array of symptoms that are known to compromise the physical functioning and quality of life of cancer patients. Common anemia-related symptoms include fatigue, drowsiness, depression, dyspnea, tachycardia, and dizziness.^1,3-7

Symptoms produced by cancer itself or the disease treatment (ie, side effects such as anemia) collectively compose a patient’s symptom burden.⁸ Although the occurrence of anemia-related fatigue has been described more systematically, other clinical presentations of chemotherapy-induced anemia (CIA) are not well characterized. Furthermore, the overall symptom burdens associated with different ranges of hemoglobin (Hb) concentrations have also not been well reported. Although various tools have been developed to facilitate the reporting of fatigue and other symptoms experienced by patients with CIA, such as the Functional Assessment of Cancer Therapy-Anemia (FACT-An) questionnaire and the MD Anderson Symptom Inventory (MDASI),^9-11 these questionnaires have not been extensively used outside of the research context. As such, knowledge on symptom burdens associated with CIA in real-world patient populations remains lacking.

Given the common occurrence of CIA, management of CIA and associated symptoms plays an important role to patients’ quality of life during cancer treatment. Symptom control is often the main goal for patients with stage IV cancers, as treatment for disease is most likely palliative or noncurative. To facilitate supportive care planning, it is important to understand patient symptom burdens as chemotherapy progresses over cycles and Hb levels decline. We conducted a comprehensive medical record review study in patients diagnosed with stage IV non-Hodgkin lymphoma (NHL), breast cancer, and lung cancers at Kaiser Permanente Southern California (KPSC), a large community-based health care delivery system. The objective of this study was to report the occurrence of CIA-related symptoms throughout the course of chemotherapy and by Hb levels.
 

Methods

Study setting and population

KPSC is an integrated managed-care organization that provides comprehensive health services for 4 million racially, ethnically, and socioeconomically diverse members who broadly represent the population in Southern California.¹² The organization maintains electronic records of health care received by its members, including physician record notes and clinical databases such as laboratory test results, diagnosis codes, medical procedures, medication dispenses, and disease registries. KPSC’s cancer registry is Surveillance, Epidemiology, and End Results, which is affiliated and routinely collects information on age, sex, race and/or ethnicity, cancer type, histology, and stage at diagnosis.

Patients who met the following inclusion criteria were included in this study: diagnosed with stage IV NHL, breast cancer, or lung cancer at age 18 years or older at KPSC between March 25, 2010 and December 31, 2012; initiated myelosuppressive chemotherapy at KPSC before June 30, 2013 (only the first chemotherapy course was included in this evaluation); and had at least 1 Hb measurement during the course of chemotherapy. Of those who met the inclusion criteria, patients who met the following criteria were excluded if they had less than 12 months KPSC membership before start of chemotherapy, missing information on cancer stage or chemotherapy regimen/agents, a diagnosis of myelodysplastic syndrome before chemotherapy initiation, a diagnosis of inherited anemia, an Hb concentration <10 g/L within 3 months before chemotherapy initiation, a transfusion within 2 weeks before chemotherapy initiation, radiation within 4 months before chemotherapy initiation, or bone marrow transplantation within 12 months before chemotherapy initiation or during the chemotherapy course. These exclusion criteria were applied to evaluate symptom burdens most likely related to CIA as opposed to other cancer treatment or pre-existing anemia.

CIA in this study was defined as moderate to severe anemia with Hb <10 g/dL after chemotherapy initiation. Based on this definition for CIA, all patients who developed CIA between the first chemotherapy administration to 60 days after the last dose of chemotherapy were included for the record review. In addition, a random sample of 100 patients who did not develop CIA (ie, did not reach an Hb <10 g/dL during chemotherapy) but otherwise met study eligibility criteria was also reviewed to serve as a comparison group. Of those, 2 patients were subsequently excluded after record review because of findings of ineligibility, so only 98 patients were presented. The large number of patients (ie, >4,000) who did not develop CIA made record review of all patients infeasible.
 

Data collection

Data on anemia-related symptoms or signs and anemia-related comorbidities (Table 1) were collected by standardized review of physician record notes in the electronic medical records. A set of 24 anemia-related symptoms were identified based on the literature and clinical expertise and included abdominal pain, blurred vision/double vision/loss of vision, cold intolerance/coldness in hands or feet, depression/anxiety, diarrhea, dizziness/lightheadedness, dyspnea/shortness of breath/tachypnea, edema, fatigue, headache, heart failure, heat intolerance, hypotension, insomnia, leg pain, loss of appetite, nausea/vomiting, pale skin, palpitations/tachycardia, paralysis/ataxia/numbness or tingling in extremities, pectoral angina/chest pain, sweating/diaphoresis, syncope, and vertigo. Record review period was defined as 1 month before chemotherapy to 60 days after the last dose of chemotherapy in the first course. To understand the development of new symptoms during chemotherapy treatment, pre-existing symptoms documented within 1 month before chemotherapy initiation were recorded. The entire record review process was standardized between 2 trained abstractors, including the training, instruction manual, ongoing feedback, abstraction form/database, and coding.

The data elements extracted included the date the symptom was documented, date the symptom started, symptom duration (when available), and any relevant comments regarding the symptom (ie, if dyspnea was at rest or on exertion, whether the symptom was a side effect caused by chemotherapy, or change in symptom severity). Ten percent of the records were reviewed independently by 2 abstractors to ensure quality control. Additional quality control measures included SAS algorithms (SAS Institute, Inc., Cary, North Carolina) to check reasonability and logical consistency in the abstracted data.

Patient demographic characteristics, cancer stage, additional selected comorbidities (Table 1), chemotherapy information, Hb test results, and anemia treatment, including erythrocyte stimulating agent (ESA) use and red blood cell transfusion, were collected using KPSC’s cancer registry and clinical databases. Anemia was defined by severity as grade 1 (10 g/dL to lower limit of normal, ie, 14 g/dL for men and 12 g/dL for women), grade 2 (8.0-9.9 g/dL), grade 3 (6.5-7.9 g/dL), and grade 4 (<6.5 g/dL) following the National Cancer Institute’s Common Terminology Criteria for Adverse Events.¹³

Statistical analysis

Distributions of demographic, cancer, and treatment characteristics were calculated by CIA status, overall and by cancer type. Differences between patients who did and did not develop CIA were assessed using chi-square test and Kruskal-Wallis test. For those who developed CIA, the distribution of the worst anemia grade was also calculated for each cycle of chemotherapy.

Next, the distributions for the following symptom categories were calculated in the 2 study samples defined by CIA status: pre-existing symptoms that occurred before chemotherapy, any symptoms during chemotherapy (ie, whether they started before chemotherapy), and incident symptoms during chemotherapy (ie, new symptoms that only started after chemotherapy). Specifically, the proportion of patients with each individual symptom and the distribution of the number of symptoms per patient were calculated. Differences in symptom distribution by CIA status were assessed using chi-square test.

The distribution of symptoms in each chemotherapy cycle was calculated up to 6 chemotherapy cycles (as >80% of the patients only had treatment up to 6 cycles) in the 2 study samples defined by CIA status. For this analysis, a symptom was “mapped” to a cycle if the date (or date range) of the symptom fell within the date range of that chemotherapy cycle. In patients who developed CIA, the distribution of symptoms was also calculated by anemia grade. This was again done on the chemotherapy cycle level. For each chemotherapy cycle, an anemia grade was assigned (no anemia or anemia grade 1, 2, 3, and 4) using the lowest Hb measurement in that cycle. Symptoms that occurred in a chemotherapy cycle were then “mapped” to the anemia grade of that cycle. Some patients had more than 1 anemia event of the same grade (eg, if a patient’s grade 2 anemia persist across cycles). For these patients, we randomly selected only 1 anemia event of the same grade from each patient to be included in this analysis. Patients could still contribute multiple events of different grades to this analysis. We calculated the mean number of symptoms per patient for each anemia grade (ie, 1-4) separately. Because of the small number of patients who developed grade 4 anemia (n = 11), they were combined with the grade 3 patients when the distributions of individual symptoms were evaluated.

All analyses were repeated stratified by gender. P values for differences between men and women were calculated using chi-square test or t test. All analyses were conducted using SAS version 9.3.
 

Results

A total of 402 stage IV NHL, breast, and lung cancer patients who developed CIA and 98 patients who did not develop CIA during the first course of chemotherapy were included (Figure 1).

Table 3 shows the number and proportion of study patients with each of the symptoms documented before and after chemotherapy initiation for the 2 study samples. Patients who developed CIA had statistically significantly more pre-existing symptoms, incident symptoms, or any symptoms that occurred during chemotherapy compared with patients who did not develop CIA. The mean number of pre-existing symptoms was 1.7 (standard deviation [SD], 2.0) for those with CIA and 1.2 (SD, 1.5) for those without CIA (P = .04). The mean number of symptoms that occurred during chemotherapy was 6.8 (SD, 3.4) and 4.1 (SD, 2.7), respectively (P < .01). Of individual symptoms, fatigue was the most commonly documented symptom during chemotherapy in patients who developed CIA, noted in 90% of the study sample (Table 3). Dyspnea/shortness of breath (58%), nausea/vomiting (56%), and loss of appetite (56%) were documented in 50% or more of these patients. Abdominal pain (35%), depression/anxiety (43%), dizziness/lightheadedness (30%), edema (39%), palpitations/tachycardia (34%), and pectoral angina/chest pain (34%) were documented in 30% or more of these patients. In patients who did not develop CIA, fatigue remained the most prevalent symptom (77% of the patients). Other than fatigue, only dyspnea/shortness of breath (41%), nausea/vomiting (43%) and paralysis/ataxia/tingling in extremities (33%) were noted in 30% or more of this study sample.

Discussion

In this study, we described the number and type of symptoms documented in the medical record notes among stage IV NHL, breast cancer, and lung cancer patients who did or did not develop CIA during chemotherapy. Patients who developed CIA had significantly greater numbers of different symptoms documented during chemotherapy than those who did not develop CIA (6.8 vs 4.1). This difference is clinically significant because most symptoms described in this study can be expected to have a negative impact on a patient’s quality of life. In patients who developed CIA, fatigue was the most commonly documented symptom, noted for 90% of the study population. In addition to fatigue, many other symptoms were noted in a large proportion of patients. In contrast, in patients who did not develop CIA, only a few symptoms (including fatigue) were more commonly noted in this sample. We observed more symptoms in chemotherapy cycles with higher grades of anemia. Of the symptoms examined, abdominal pain, depression, diarrhea, dizziness/lightheadedness, dyspnea, edema, fatigue, heart failure, headache, hypotension, insomnia, leg pain, loss of appetite, nausea/vomiting, pale skin, pectoral angina, sweating, and syncope particularly demonstrated a clearly increasing prevalence with declining Hb level. We also reported that patients who developed severe anemia (grades 3 and 4) experienced an average of 5 to 6 different symptoms at the time of the anemia episode. These data demonstrated a significant symptom burden in cancer patients with CIA seen in community-based oncology practices. Findings on the types of symptoms most commonly noted in various grades of CIA episodes provided some guidance for supportive care planning. As previous studies have shown a reduction in symptom burden after anemia treatment in patients with CIA,^14-16 our results support the idea of early lab draws and active management of CIA in maintaining quality of life in cancer patients undergoing chemotherapy.

Our findings on the prevalence of fatigue are in line with other studies in the literature. Maxwell reported that the prevalence of fatigue was 80% to 96% in cancer patients.¹⁷ Cella and colleagues found that using FACT-General questionnaire, 75% of cancer patients reported fatigue.¹¹ The comparability of our estimate and those found in studies based on patient self-report offered some assurance of the validity of assessing symptom prevalence through physician record notes. In addition to fatigue, we described prevalence of 23 additional symptoms, most of which have not been extensively studied in the literature. Gabrilove and colleagues found that a substantial proportion of patients with CIA had moderate to severe score for lack of appetite (36%) and disturbed sleep (41%) using the MDASI.¹⁰ The prevalence of loss of appetite and insomnia was around 50% and 25%, respectively, in our study samples. A 2013 systematic review of 21 multinational studies reported the pooled prevalence of several nonfatigue symptoms in cancer patients including headache (23%), sleep disturbance/insomnia (49%), appetite changes (45%), nausea/vomiting (26%), diarrhea (15%), depression (34%), dyspnea (44%), dizziness (26%), numbness/tingling (42%), edema (14%), and sweating (28%).¹⁸ Our prevalence estimates in patients with CIA for most of these symptoms were higher, likely because Reilly and colleagues used source studies that included any cancer patients undergoing treatment and not just those with CIA. Our findings on the increased symptom burden in patients who experienced episodes of advanced anemia compared with patients with mild anemia were also consistent with the literature. To this end, several studies using MDASI or the FACT-An reported differential symptom burdens by Hb level based on patient self-report,^10,11,19 including data on improvement in symptom burden and quality of life after anemia was amended with the use of ESA.^20,21

We found that the number of pre-existing symptoms was significantly higher in patients who went on to develop CIA than in patients who did not develop CIA. Specifically, fatigue, loss of appetite, and pale skin before chemotherapy seemed to be significantly more common in patients who went on to develop CIA. This finding suggested that presentation of these symptoms before chemotherapy initiation may be a predictor for developing moderate or severe anemia during treatment. This is a novel hypothesis, as no studies have evaluated the relationship between pretreatment symptom and risk of CIA. However, our study was not designed to address this specific question. Additional investigation is needed to further shed light on whether the occurrence of anemia-related symptoms in nonanemic patients can be used to effectively risk-stratify patients for subsequent CIA.

Contrary to our expectation, the prevalence of most symptoms did not clearly increase as chemotherapy progressed. There are several possible explanations to this phenomenon, with the most likely being related to reporting of anemia-related symptoms. For example, patients might stop reporting the same symptom repeatedly or become adjusted to the new Hb levels, leading to less symptom manifestation. Clinicians may also be less likely to ask about symptoms in later treatment cycles and/or to document chronic symptoms. Several symptoms were rarely documented altogether, such as cold intolerance, heat intolerance, heart failure, and vertigo. Symptoms reported in earlier cycles could also be managed successfully. Another possible explanation is differential loss of follow-up. Patients who experienced severe adverse events or symptoms may terminate treatment prematurely. Thus, symptom burden found toward later cycles may not represent the true symptom burden should everyone who initiated the chemotherapy treatment complete all planned cycles.
 

Limitations

In addition to the limitations already discussed, there are several others that should be considered when interpreting our results. We did not have a consistent measure of symptom severity in the medical records. Duration of symptoms was also often poorly documented by physicians. Therefore, our results are not directly comparable with studies such as the MDASI that incorporate severity or duration in their prevalence measure. There may also be “reporting bias” by the clinicians owing to different perceived levels of severity or clinical relevance of the different symptoms. As a result, some symptoms may be underdocumented, leading to undercounting.

We also did not distinguish the exact cause of the symptoms (ie, owing to anemia, cancer, chemotherapy itself, or other chemotherapy-induced complications), as it was not possible to reliably ascertain the cause from record review. Furthermore, symptom assessment was not separately performed for grade 4 anemia because of the small number of events in the study population. We also did not plan to evaluate the impact of anemia treatment on symptom burden, as our goal was to comprehensively describe a wide spectrum of symptoms experienced by patients with different Hb levels. However, previous studies have shown the benefit of treatments that correct CIA in symptom management.^14-16 Finally, this study does not inform about the relative importance of these symptoms to patients’ quality of life. To this end, a qualitative study found fatigue, shortness of breath, and lightheadedness/dizziness to be the most important symptoms ranked by patients with CIA.²²

Despite the potential limitations, our study has several important strengths. In addition to fatigue, patients with CIA suffer from a wide range of other anemia-related symptoms, but data on the prevalence of these symptoms have been lacking. To our knowledge, this is among the first studies that collected data on a comprehensive list of symptoms and provided detailed analysis by chemotherapy cycle and anemia grade. The combined use of KPSC’s clinical databases and medical record review allowed us to provide detailed characterization of the study population in terms of their treatment history, history of comorbidities, and laboratory data.
 

Conclusions

Our data provide physicians a comprehensive picture of prevalence of various types of symptoms and how symptom burden evolves as chemotherapy cycle and anemia severity progress. High-grade CIA correlates with an increased symptom burden. Such an understanding can be crucial in facilitating supportive care planning by helping physicians anticipate the timing and proactively determine the management approach of chemotherapy-related anemia and its symptoms.

SAN ANTONIO – Programmed death-ligand 1 (PD-L1) expression on tumor-infiltrating immune cells is the best predictor of response to atezolizumab + nab-paclitaxel in patients with untreated metastatic triple-negative breast cancer, according to exploratory efficacy analyses of data from the phase 3 IMpassion130 trial.

The analyses of data for the 902 patients randomized to receive the PD-L1 inhibitor atezolizumab (Tecentriq) plus nanoparticle albumin-bound (nab)–paclitaxel or placebo plus nab-palcitaxel for the study also showed consistency between local and central estrogen-receptor, progesterone-receptor, and human epidermal growth factor–receptor 2 testing, Leisha A. Emens, MD, reported at the San Antonio Breast Cancer Symposium.

“IMpassion130 is the first phase 3 study to demonstrate a benefit from [atezolizumab + nab-paclitaxel] in metastatic triple-negative breast cancer (mTNBC),” said Dr. Emens, professor of medicine in hematology/oncology, coleader of the Hillman Cancer Immunology and Immunotherapy Program, and director of translational immunotherapy for the Women’s Cancer Research Center at the University of Pittsburgh Medical Center.

She explained that progression-free survival (PFS) was significantly better in PD-L1–positive mTNBC patients treated with the atezolizumab + nab-paclitaxel, than in those who received placebo + nab-paclitaxel (hazard ratios in the intent-to-treat population, 0.8 and 0.62, respectively).

At the first interim overall survival analysis, a clinically meaningful improvement in OS was seen in PD-L1–positive patients in the treatment group (HR, 0.62; median OS improvement from 15.5 months with placebo to 25 months), she added.

In exploratory analyses, Dr. Emens and her colleagues sought to evaluate whether preexisting immune biology is associated with clinical benefit from atezolizumab + nab-paclitaxel, as has been demonstrated in studies of other agents that target the PD-1 pathway in other cancer types of cancer. They also assessed BRCA 1/2 mutation status as a biomarker for response.

“In patients enrolled on the IMpassion130 trial we found that PD-L1 in triple-negative breast cancer was expressed primarily on tumor-infiltrating immune cells,” she said. “In contrast to this, we found a very low rate of PD-L1 expression specifically on tumor cells across the patient population.”

Looking at both of those biomarkers together showed that a majority of patients with expression of PD-L1 on tumor cells were included in the PD-L1 immune cell–positive population, with only 2% having PD-L1 expression exclusively on their tumor cells.

Data previously reported at the European Society for Medical Oncology and published in the New England Journal of Medicine showed a PFS benefit, as well as a clinically meaningful improvement in OS of nearly 10 months, specifically in patients with PD-L1 immune cell–positive lesions treated with atezolizumab + nab-paclitaxel, she noted.

“In data presented for the first time today you can see that PD-L1–negative patients derive no overall survival benefit as there was no treatment effect with this therapy combination,” she said.

A trend was seen toward an association between immune cell positivity and poor prognosis, but this was not statistically significant, she said.

“Taken together, these data definitively show that PD-L1 immune cell positivity is predictive of both progression-free and overall survival benefit with atezolizumab + nab-paclitaxel,” she said.

She and her colleagues also looked at the level of PD-L1 expression in immune cells to assess whether there is a threshold that might be required.

“As long as there was a PD-L1 expression level of 1% or more in the immune cells, there was a significant progression-free and overall survival benefit for patients treated with atezolizumab + nab-paclitaxel. This suggests that this expression of over 1% will represent a threshold for identifying those patients who are likely to benefit from this combination,” she said.

Further assessment by CD8 T-cell status showed that patients who had CD8-positive T cells but who were PD-L1 immune cell negative had no benefit from atezolizumab + nab-paclitaxel, whereas those who were positive for both CD8 and PD-L1 expression on their immune cells derived significant PFS and OS benefit (HR, 0.89 and 0.77, respectively).

“So patients with CD8-positive tumors derive clinical benefit only if their tumors are also PD-L1-positive,” she said.

Similarly, no clinical benefit was seen in patients with stromal tumor-infiltrating lymphocyte (TIL)–positive tumors but who were PD-L1-negative, whereas those with stromal TIL-positive PD-L1–positive tumors derived significant PFS and OS benefit (HRs, 0.99 and 1.53, respectively), and this was also seen in the 15% of evaluable patients who had BRCA mutations.

“In patients who were BRCA mutated, but who were PD-L1 immune cell negative, there was no association of progression-free survival or an overall survival benefit [with atezolizumab + nab-paclitaxel]. In contrast, in patients who were BRCA mutated but PD-L1 immune cell positive ... there was an association with progression-free survival and a trend toward overall survival,” she said, noting that while the BRCA mutation findings are limited by small numbers, “they do show that mutations in BRCA and PD-L1 expression in immune cells are independent biomarkers; patients with BRCA1 or 2 mutations derive clinical benefit only if their tumors are also PD-L1 positive.”

“In this phase 3 IMpassion130 study, PD-L1 expression on immune cells is a predictive biomarker for selecting patients who benefit clinically during first-line treatment with atezolizumab + nab-paclitaxel for metastatic triple-negative breast cancer,” she concluded, adding that “patients with newly diagnosed metastatic and unresectable locally advanced triple-negative breast cancer should be routinely tested for their PD-L1 immune cell status to determine if they might benefit from the combination of atezolizumab + nab-paclitaxel.

IMpassion130 was sponsored by Hoffman-La Roche. Dr. Emens reported receiving royalties and consulting fees from several companies. She has contracts with Roche/Genentech, Corvus, AstraZeneca, and EMD Serono, and ownership in Molecuvax. She receives other support from DSMB and Syndax, and has received grants from Aduro Biotech, Merck, Maxcyte, and the Breast Cancer Research Foundation. She also reported serving as a member of the Food and Drug Administration Advisory Committee on Tissue, Cell, and Gene Therapies, and is a member of the board of directors for the Society of Immunotherapy for Cancer.

SOURCE: Emens L et al. SABCS 2018, Abstract GS1-04.

SAN ANTONIO – Programmed death-ligand 1 (PD-L1) expression on tumor-infiltrating immune cells is the best predictor of response to atezolizumab + nab-paclitaxel in patients with untreated metastatic triple-negative breast cancer, according to exploratory efficacy analyses of data from the phase 3 IMpassion130 trial.

The analyses of data for the 902 patients randomized to receive the PD-L1 inhibitor atezolizumab (Tecentriq) plus nanoparticle albumin-bound (nab)–paclitaxel or placebo plus nab-palcitaxel for the study also showed consistency between local and central estrogen-receptor, progesterone-receptor, and human epidermal growth factor–receptor 2 testing, Leisha A. Emens, MD, reported at the San Antonio Breast Cancer Symposium.

“IMpassion130 is the first phase 3 study to demonstrate a benefit from [atezolizumab + nab-paclitaxel] in metastatic triple-negative breast cancer (mTNBC),” said Dr. Emens, professor of medicine in hematology/oncology, coleader of the Hillman Cancer Immunology and Immunotherapy Program, and director of translational immunotherapy for the Women’s Cancer Research Center at the University of Pittsburgh Medical Center.

She explained that progression-free survival (PFS) was significantly better in PD-L1–positive mTNBC patients treated with the atezolizumab + nab-paclitaxel, than in those who received placebo + nab-paclitaxel (hazard ratios in the intent-to-treat population, 0.8 and 0.62, respectively).

At the first interim overall survival analysis, a clinically meaningful improvement in OS was seen in PD-L1–positive patients in the treatment group (HR, 0.62; median OS improvement from 15.5 months with placebo to 25 months), she added.

In exploratory analyses, Dr. Emens and her colleagues sought to evaluate whether preexisting immune biology is associated with clinical benefit from atezolizumab + nab-paclitaxel, as has been demonstrated in studies of other agents that target the PD-1 pathway in other cancer types of cancer. They also assessed BRCA 1/2 mutation status as a biomarker for response.

“In patients enrolled on the IMpassion130 trial we found that PD-L1 in triple-negative breast cancer was expressed primarily on tumor-infiltrating immune cells,” she said. “In contrast to this, we found a very low rate of PD-L1 expression specifically on tumor cells across the patient population.”

Looking at both of those biomarkers together showed that a majority of patients with expression of PD-L1 on tumor cells were included in the PD-L1 immune cell–positive population, with only 2% having PD-L1 expression exclusively on their tumor cells.

Data previously reported at the European Society for Medical Oncology and published in the New England Journal of Medicine showed a PFS benefit, as well as a clinically meaningful improvement in OS of nearly 10 months, specifically in patients with PD-L1 immune cell–positive lesions treated with atezolizumab + nab-paclitaxel, she noted.

“In data presented for the first time today you can see that PD-L1–negative patients derive no overall survival benefit as there was no treatment effect with this therapy combination,” she said.

A trend was seen toward an association between immune cell positivity and poor prognosis, but this was not statistically significant, she said.

“Taken together, these data definitively show that PD-L1 immune cell positivity is predictive of both progression-free and overall survival benefit with atezolizumab + nab-paclitaxel,” she said.

She and her colleagues also looked at the level of PD-L1 expression in immune cells to assess whether there is a threshold that might be required.

“As long as there was a PD-L1 expression level of 1% or more in the immune cells, there was a significant progression-free and overall survival benefit for patients treated with atezolizumab + nab-paclitaxel. This suggests that this expression of over 1% will represent a threshold for identifying those patients who are likely to benefit from this combination,” she said.

Further assessment by CD8 T-cell status showed that patients who had CD8-positive T cells but who were PD-L1 immune cell negative had no benefit from atezolizumab + nab-paclitaxel, whereas those who were positive for both CD8 and PD-L1 expression on their immune cells derived significant PFS and OS benefit (HR, 0.89 and 0.77, respectively).

“So patients with CD8-positive tumors derive clinical benefit only if their tumors are also PD-L1-positive,” she said.

Similarly, no clinical benefit was seen in patients with stromal tumor-infiltrating lymphocyte (TIL)–positive tumors but who were PD-L1-negative, whereas those with stromal TIL-positive PD-L1–positive tumors derived significant PFS and OS benefit (HRs, 0.99 and 1.53, respectively), and this was also seen in the 15% of evaluable patients who had BRCA mutations.

“In patients who were BRCA mutated, but who were PD-L1 immune cell negative, there was no association of progression-free survival or an overall survival benefit [with atezolizumab + nab-paclitaxel]. In contrast, in patients who were BRCA mutated but PD-L1 immune cell positive ... there was an association with progression-free survival and a trend toward overall survival,” she said, noting that while the BRCA mutation findings are limited by small numbers, “they do show that mutations in BRCA and PD-L1 expression in immune cells are independent biomarkers; patients with BRCA1 or 2 mutations derive clinical benefit only if their tumors are also PD-L1 positive.”

“In this phase 3 IMpassion130 study, PD-L1 expression on immune cells is a predictive biomarker for selecting patients who benefit clinically during first-line treatment with atezolizumab + nab-paclitaxel for metastatic triple-negative breast cancer,” she concluded, adding that “patients with newly diagnosed metastatic and unresectable locally advanced triple-negative breast cancer should be routinely tested for their PD-L1 immune cell status to determine if they might benefit from the combination of atezolizumab + nab-paclitaxel.

IMpassion130 was sponsored by Hoffman-La Roche. Dr. Emens reported receiving royalties and consulting fees from several companies. She has contracts with Roche/Genentech, Corvus, AstraZeneca, and EMD Serono, and ownership in Molecuvax. She receives other support from DSMB and Syndax, and has received grants from Aduro Biotech, Merck, Maxcyte, and the Breast Cancer Research Foundation. She also reported serving as a member of the Food and Drug Administration Advisory Committee on Tissue, Cell, and Gene Therapies, and is a member of the board of directors for the Society of Immunotherapy for Cancer.

SOURCE: Emens L et al. SABCS 2018, Abstract GS1-04.

SAN ANTONIO – Programmed death-ligand 1 (PD-L1) expression on tumor-infiltrating immune cells is the best predictor of response to atezolizumab + nab-paclitaxel in patients with untreated metastatic triple-negative breast cancer, according to exploratory efficacy analyses of data from the phase 3 IMpassion130 trial.

The analyses of data for the 902 patients randomized to receive the PD-L1 inhibitor atezolizumab (Tecentriq) plus nanoparticle albumin-bound (nab)–paclitaxel or placebo plus nab-palcitaxel for the study also showed consistency between local and central estrogen-receptor, progesterone-receptor, and human epidermal growth factor–receptor 2 testing, Leisha A. Emens, MD, reported at the San Antonio Breast Cancer Symposium.

“IMpassion130 is the first phase 3 study to demonstrate a benefit from [atezolizumab + nab-paclitaxel] in metastatic triple-negative breast cancer (mTNBC),” said Dr. Emens, professor of medicine in hematology/oncology, coleader of the Hillman Cancer Immunology and Immunotherapy Program, and director of translational immunotherapy for the Women’s Cancer Research Center at the University of Pittsburgh Medical Center.

She explained that progression-free survival (PFS) was significantly better in PD-L1–positive mTNBC patients treated with the atezolizumab + nab-paclitaxel, than in those who received placebo + nab-paclitaxel (hazard ratios in the intent-to-treat population, 0.8 and 0.62, respectively).

At the first interim overall survival analysis, a clinically meaningful improvement in OS was seen in PD-L1–positive patients in the treatment group (HR, 0.62; median OS improvement from 15.5 months with placebo to 25 months), she added.

In exploratory analyses, Dr. Emens and her colleagues sought to evaluate whether preexisting immune biology is associated with clinical benefit from atezolizumab + nab-paclitaxel, as has been demonstrated in studies of other agents that target the PD-1 pathway in other cancer types of cancer. They also assessed BRCA 1/2 mutation status as a biomarker for response.

“In patients enrolled on the IMpassion130 trial we found that PD-L1 in triple-negative breast cancer was expressed primarily on tumor-infiltrating immune cells,” she said. “In contrast to this, we found a very low rate of PD-L1 expression specifically on tumor cells across the patient population.”

Looking at both of those biomarkers together showed that a majority of patients with expression of PD-L1 on tumor cells were included in the PD-L1 immune cell–positive population, with only 2% having PD-L1 expression exclusively on their tumor cells.

Data previously reported at the European Society for Medical Oncology and published in the New England Journal of Medicine showed a PFS benefit, as well as a clinically meaningful improvement in OS of nearly 10 months, specifically in patients with PD-L1 immune cell–positive lesions treated with atezolizumab + nab-paclitaxel, she noted.

“In data presented for the first time today you can see that PD-L1–negative patients derive no overall survival benefit as there was no treatment effect with this therapy combination,” she said.

A trend was seen toward an association between immune cell positivity and poor prognosis, but this was not statistically significant, she said.

“Taken together, these data definitively show that PD-L1 immune cell positivity is predictive of both progression-free and overall survival benefit with atezolizumab + nab-paclitaxel,” she said.

She and her colleagues also looked at the level of PD-L1 expression in immune cells to assess whether there is a threshold that might be required.

“As long as there was a PD-L1 expression level of 1% or more in the immune cells, there was a significant progression-free and overall survival benefit for patients treated with atezolizumab + nab-paclitaxel. This suggests that this expression of over 1% will represent a threshold for identifying those patients who are likely to benefit from this combination,” she said.

Further assessment by CD8 T-cell status showed that patients who had CD8-positive T cells but who were PD-L1 immune cell negative had no benefit from atezolizumab + nab-paclitaxel, whereas those who were positive for both CD8 and PD-L1 expression on their immune cells derived significant PFS and OS benefit (HR, 0.89 and 0.77, respectively).

“So patients with CD8-positive tumors derive clinical benefit only if their tumors are also PD-L1-positive,” she said.

Similarly, no clinical benefit was seen in patients with stromal tumor-infiltrating lymphocyte (TIL)–positive tumors but who were PD-L1-negative, whereas those with stromal TIL-positive PD-L1–positive tumors derived significant PFS and OS benefit (HRs, 0.99 and 1.53, respectively), and this was also seen in the 15% of evaluable patients who had BRCA mutations.

“In patients who were BRCA mutated, but who were PD-L1 immune cell negative, there was no association of progression-free survival or an overall survival benefit [with atezolizumab + nab-paclitaxel]. In contrast, in patients who were BRCA mutated but PD-L1 immune cell positive ... there was an association with progression-free survival and a trend toward overall survival,” she said, noting that while the BRCA mutation findings are limited by small numbers, “they do show that mutations in BRCA and PD-L1 expression in immune cells are independent biomarkers; patients with BRCA1 or 2 mutations derive clinical benefit only if their tumors are also PD-L1 positive.”

“In this phase 3 IMpassion130 study, PD-L1 expression on immune cells is a predictive biomarker for selecting patients who benefit clinically during first-line treatment with atezolizumab + nab-paclitaxel for metastatic triple-negative breast cancer,” she concluded, adding that “patients with newly diagnosed metastatic and unresectable locally advanced triple-negative breast cancer should be routinely tested for their PD-L1 immune cell status to determine if they might benefit from the combination of atezolizumab + nab-paclitaxel.

IMpassion130 was sponsored by Hoffman-La Roche. Dr. Emens reported receiving royalties and consulting fees from several companies. She has contracts with Roche/Genentech, Corvus, AstraZeneca, and EMD Serono, and ownership in Molecuvax. She receives other support from DSMB and Syndax, and has received grants from Aduro Biotech, Merck, Maxcyte, and the Breast Cancer Research Foundation. She also reported serving as a member of the Food and Drug Administration Advisory Committee on Tissue, Cell, and Gene Therapies, and is a member of the board of directors for the Society of Immunotherapy for Cancer.

SOURCE: Emens L et al. SABCS 2018, Abstract GS1-04.

SAN ANTONIO – A phase 3 randomized controlled trial jointly conducted by GEICAM and CIBOMA is negative, showing that adding adjuvant capecitabine (Xeloda) to surgery and standard chemotherapy does not improve disease-free or overall survival in women with early-stage triple-negative breast cancer, reported lead investigator Miguel Martín, MD, PhD.

At the San Antonio Breast Cancer Symposium, he discussed the overall findings and intriguing subgroup results suggesting that there was a benefit in women with tumors having the nonbasal phenotype. Dr. Martín also detailed implications in the context of the CREATE-X trial findings and the era of personalized medicine, and outlined next avenues of research.

The trial was supported by Roche, which also provided capecitabine. Dr. Martín disclosed that he has received speakers honoraria from Pfizer and Lilly; honoraria for participation in advisory boards from AstraZeneca, Novartis, Roche-Genentech, Pfizer, GlaxoSmithKline, PharmaMar, Taiho Oncology, and Lilly; and research grants from Novartis and Roche.

SAN ANTONIO – A phase 3 randomized controlled trial jointly conducted by GEICAM and CIBOMA is negative, showing that adding adjuvant capecitabine (Xeloda) to surgery and standard chemotherapy does not improve disease-free or overall survival in women with early-stage triple-negative breast cancer, reported lead investigator Miguel Martín, MD, PhD.

At the San Antonio Breast Cancer Symposium, he discussed the overall findings and intriguing subgroup results suggesting that there was a benefit in women with tumors having the nonbasal phenotype. Dr. Martín also detailed implications in the context of the CREATE-X trial findings and the era of personalized medicine, and outlined next avenues of research.

The trial was supported by Roche, which also provided capecitabine. Dr. Martín disclosed that he has received speakers honoraria from Pfizer and Lilly; honoraria for participation in advisory boards from AstraZeneca, Novartis, Roche-Genentech, Pfizer, GlaxoSmithKline, PharmaMar, Taiho Oncology, and Lilly; and research grants from Novartis and Roche.

SAN ANTONIO – A phase 3 randomized controlled trial jointly conducted by GEICAM and CIBOMA is negative, showing that adding adjuvant capecitabine (Xeloda) to surgery and standard chemotherapy does not improve disease-free or overall survival in women with early-stage triple-negative breast cancer, reported lead investigator Miguel Martín, MD, PhD.

At the San Antonio Breast Cancer Symposium, he discussed the overall findings and intriguing subgroup results suggesting that there was a benefit in women with tumors having the nonbasal phenotype. Dr. Martín also detailed implications in the context of the CREATE-X trial findings and the era of personalized medicine, and outlined next avenues of research.

The trial was supported by Roche, which also provided capecitabine. Dr. Martín disclosed that he has received speakers honoraria from Pfizer and Lilly; honoraria for participation in advisory boards from AstraZeneca, Novartis, Roche-Genentech, Pfizer, GlaxoSmithKline, PharmaMar, Taiho Oncology, and Lilly; and research grants from Novartis and Roche.

SAN ANTONIO – After a 2-year follow-up, the efficacy and cardiac toxicity profile between CT-P6, a trastuzumab biosimilar candidate, and trastuzumab as neoadjuvant and then adjuvant therapy for patients with early HER2-positive breast cancer remains consistent with previous results.

Similarity in safety and efficacy at 1 year was previously demonstrated in the phase 3 trial, as well as similarity in cardiac toxicity at a median of 19 months. Updated disease-free survival, overall survival, and cardiac toxicity with a median follow-up of 2 years will be presented by Francisco J. Esteva, MD, PhD, of the Laura & Isaac Perlmutter Cancer Center at NYU Langone Health, New York, in a poster presentation at the San Antonio Breast Cancer Symposium.

For the trial, 549 patients with HER2-positive early breast cancer were randomized to receive CT-P6 (n = 271) or trastuzumab (n = 278) in combination with docetaxel (cycles 1-4) and 5-fluorouracil, epirubicin, and cyclophosphamide (cycles 5-8). CT-P6 or trastuzumab was administered at 8 mg/kg (cycle 1 only) followed by 6 mg/kg every 3 weeks. After surgery, patients received CT-P6 or trastuzumab monotherapy and then entered the follow-up period.

A total of 528 patients entered the follow-up period, with a median duration of 27 months. Disease-free and overall survival were similar in the two arms in both the per-protocol set and the intention-to-treat set. In the intention-to-treat set, the 2-year disease-free survival was 86% (95% confidence interval, 80%-90%) in the CT-P6 arm and 90% (95% CI, 85%-93%) in the trastuzumab arm. Two-year overall survival was 97% (95% CI, 93%-98%) in the CT-P6 arm and 98% (95% CI, 96%-99%) in the trastuzumab arm. Median disease-free and overall survival have not been reached, according to the abstract.

No new cases of heart failure were reported during the follow-up period. Left ventricular ejection fraction was similar in both arms. The efficacy and cardiac toxicity profile between CT-P6 and trastuzumab were consistent with published data.

“CT-P6 was consistently well tolerated with a similar cardiotoxicity profile to that of trastuzumab through a long duration of follow-up,” Dr. Esteva and authors said.

The study sponsor is Celltrion, maker of CT-P6. Dr. Esteva disclosed a consulting or advisory role with Celltrion, as well as relationships with various other pharmaceutical companies.

SOURCE: Esteva FJ et al. SABCS 2018, Abstract P6-17-03.

SAN ANTONIO – After a 2-year follow-up, the efficacy and cardiac toxicity profile between CT-P6, a trastuzumab biosimilar candidate, and trastuzumab as neoadjuvant and then adjuvant therapy for patients with early HER2-positive breast cancer remains consistent with previous results.

Similarity in safety and efficacy at 1 year was previously demonstrated in the phase 3 trial, as well as similarity in cardiac toxicity at a median of 19 months. Updated disease-free survival, overall survival, and cardiac toxicity with a median follow-up of 2 years will be presented by Francisco J. Esteva, MD, PhD, of the Laura & Isaac Perlmutter Cancer Center at NYU Langone Health, New York, in a poster presentation at the San Antonio Breast Cancer Symposium.

For the trial, 549 patients with HER2-positive early breast cancer were randomized to receive CT-P6 (n = 271) or trastuzumab (n = 278) in combination with docetaxel (cycles 1-4) and 5-fluorouracil, epirubicin, and cyclophosphamide (cycles 5-8). CT-P6 or trastuzumab was administered at 8 mg/kg (cycle 1 only) followed by 6 mg/kg every 3 weeks. After surgery, patients received CT-P6 or trastuzumab monotherapy and then entered the follow-up period.

A total of 528 patients entered the follow-up period, with a median duration of 27 months. Disease-free and overall survival were similar in the two arms in both the per-protocol set and the intention-to-treat set. In the intention-to-treat set, the 2-year disease-free survival was 86% (95% confidence interval, 80%-90%) in the CT-P6 arm and 90% (95% CI, 85%-93%) in the trastuzumab arm. Two-year overall survival was 97% (95% CI, 93%-98%) in the CT-P6 arm and 98% (95% CI, 96%-99%) in the trastuzumab arm. Median disease-free and overall survival have not been reached, according to the abstract.

No new cases of heart failure were reported during the follow-up period. Left ventricular ejection fraction was similar in both arms. The efficacy and cardiac toxicity profile between CT-P6 and trastuzumab were consistent with published data.

“CT-P6 was consistently well tolerated with a similar cardiotoxicity profile to that of trastuzumab through a long duration of follow-up,” Dr. Esteva and authors said.

The study sponsor is Celltrion, maker of CT-P6. Dr. Esteva disclosed a consulting or advisory role with Celltrion, as well as relationships with various other pharmaceutical companies.

SOURCE: Esteva FJ et al. SABCS 2018, Abstract P6-17-03.

SAN ANTONIO – After a 2-year follow-up, the efficacy and cardiac toxicity profile between CT-P6, a trastuzumab biosimilar candidate, and trastuzumab as neoadjuvant and then adjuvant therapy for patients with early HER2-positive breast cancer remains consistent with previous results.

Similarity in safety and efficacy at 1 year was previously demonstrated in the phase 3 trial, as well as similarity in cardiac toxicity at a median of 19 months. Updated disease-free survival, overall survival, and cardiac toxicity with a median follow-up of 2 years will be presented by Francisco J. Esteva, MD, PhD, of the Laura & Isaac Perlmutter Cancer Center at NYU Langone Health, New York, in a poster presentation at the San Antonio Breast Cancer Symposium.

For the trial, 549 patients with HER2-positive early breast cancer were randomized to receive CT-P6 (n = 271) or trastuzumab (n = 278) in combination with docetaxel (cycles 1-4) and 5-fluorouracil, epirubicin, and cyclophosphamide (cycles 5-8). CT-P6 or trastuzumab was administered at 8 mg/kg (cycle 1 only) followed by 6 mg/kg every 3 weeks. After surgery, patients received CT-P6 or trastuzumab monotherapy and then entered the follow-up period.

A total of 528 patients entered the follow-up period, with a median duration of 27 months. Disease-free and overall survival were similar in the two arms in both the per-protocol set and the intention-to-treat set. In the intention-to-treat set, the 2-year disease-free survival was 86% (95% confidence interval, 80%-90%) in the CT-P6 arm and 90% (95% CI, 85%-93%) in the trastuzumab arm. Two-year overall survival was 97% (95% CI, 93%-98%) in the CT-P6 arm and 98% (95% CI, 96%-99%) in the trastuzumab arm. Median disease-free and overall survival have not been reached, according to the abstract.

No new cases of heart failure were reported during the follow-up period. Left ventricular ejection fraction was similar in both arms. The efficacy and cardiac toxicity profile between CT-P6 and trastuzumab were consistent with published data.

“CT-P6 was consistently well tolerated with a similar cardiotoxicity profile to that of trastuzumab through a long duration of follow-up,” Dr. Esteva and authors said.

The study sponsor is Celltrion, maker of CT-P6. Dr. Esteva disclosed a consulting or advisory role with Celltrion, as well as relationships with various other pharmaceutical companies.

SOURCE: Esteva FJ et al. SABCS 2018, Abstract P6-17-03.

SAN ANTONIO – Swapping trastuzumab out for the drug-antibody conjugate trastuzumab emtansine (T-DM1; Kadcyla) as adjuvant therapy resulted in a halving in the risk of invasive disease or death in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy, including trastuzumab.

For the primary endpoint in the KATHERINE trial of invasive disease-free survival – defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause – T-DM1 was associated with a hazard ratio of 0.50 (P less than .001).

The 3-year invasive disease-free survival rate for 743 patients treated with T-DMI 1 was 88.3%, compared with 77% for 743 patients treated with trastuzumab, reported Charles E. Geyer Jr., MD, from Virginia Commonwealth University, Richmond, at the San Antonio Breast Cancer Symposium.

In a video interview, Dr. Geyer discussed results of KATHERINE, which suggest that T-DM1 should be considered as a new standard of care in this patient population.

Dr. Geyer reported travel support from Roche and AstraZeneca, medical writing support from AbbVie and Roche, and honoraria from Celgene.

SAN ANTONIO – Swapping trastuzumab out for the drug-antibody conjugate trastuzumab emtansine (T-DM1; Kadcyla) as adjuvant therapy resulted in a halving in the risk of invasive disease or death in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy, including trastuzumab.

For the primary endpoint in the KATHERINE trial of invasive disease-free survival – defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause – T-DM1 was associated with a hazard ratio of 0.50 (P less than .001).

The 3-year invasive disease-free survival rate for 743 patients treated with T-DMI 1 was 88.3%, compared with 77% for 743 patients treated with trastuzumab, reported Charles E. Geyer Jr., MD, from Virginia Commonwealth University, Richmond, at the San Antonio Breast Cancer Symposium.

In a video interview, Dr. Geyer discussed results of KATHERINE, which suggest that T-DM1 should be considered as a new standard of care in this patient population.

Dr. Geyer reported travel support from Roche and AstraZeneca, medical writing support from AbbVie and Roche, and honoraria from Celgene.

SAN ANTONIO – Swapping trastuzumab out for the drug-antibody conjugate trastuzumab emtansine (T-DM1; Kadcyla) as adjuvant therapy resulted in a halving in the risk of invasive disease or death in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy, including trastuzumab.

For the primary endpoint in the KATHERINE trial of invasive disease-free survival – defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause – T-DM1 was associated with a hazard ratio of 0.50 (P less than .001).

The 3-year invasive disease-free survival rate for 743 patients treated with T-DMI 1 was 88.3%, compared with 77% for 743 patients treated with trastuzumab, reported Charles E. Geyer Jr., MD, from Virginia Commonwealth University, Richmond, at the San Antonio Breast Cancer Symposium.

In a video interview, Dr. Geyer discussed results of KATHERINE, which suggest that T-DM1 should be considered as a new standard of care in this patient population.

Dr. Geyer reported travel support from Roche and AstraZeneca, medical writing support from AbbVie and Roche, and honoraria from Celgene.

While the majority of the presentations at this year’s San Antonio Breast Cancer Symposium, to be held Dec. 4-8, will focus on treatments, a few will focus on the treatment decisions. One such presentation will report on the findings of the phase 3 STIC CTC trial. This trial seeks to determine if circulating tumor cells (CTC) could serve as a tool to choose between first-line hormone therapy and chemotherapy for ER-positive HER2-negative metastatic breast cancer.

In the standard arm of the trial, treatment was decided by clinicians, taking into account the criteria usually used in this setting. In the CTC arm, the type of treatment was decided by CTC count: Hormone-therapy was chosen if there were fewer than 5 CTC/7.5 mL (CellSearch technique) or chemotherapy if there were 5 or more CTC/7.5 mL. The main objective was to demonstrate the noninferiority of the CTC-based strategy for progression-free survival. The secondary clinical objectives of the French trial were to compare toxicity, quality of life, and overall survival between the two arms. The cost per progression-free life-years gained will be compared in the two arms, as well.

The results and analysis of STIC CTC will be presented by Francois-Clement Bidard, MD, PhD, of Institut Curie, Paris, and the University of Versailles (France), on Thursday, Dec. 6 at 11 a.m. CST.




 

While the majority of the presentations at this year’s San Antonio Breast Cancer Symposium, to be held Dec. 4-8, will focus on treatments, a few will focus on the treatment decisions. One such presentation will report on the findings of the phase 3 STIC CTC trial. This trial seeks to determine if circulating tumor cells (CTC) could serve as a tool to choose between first-line hormone therapy and chemotherapy for ER-positive HER2-negative metastatic breast cancer.

In the standard arm of the trial, treatment was decided by clinicians, taking into account the criteria usually used in this setting. In the CTC arm, the type of treatment was decided by CTC count: Hormone-therapy was chosen if there were fewer than 5 CTC/7.5 mL (CellSearch technique) or chemotherapy if there were 5 or more CTC/7.5 mL. The main objective was to demonstrate the noninferiority of the CTC-based strategy for progression-free survival. The secondary clinical objectives of the French trial were to compare toxicity, quality of life, and overall survival between the two arms. The cost per progression-free life-years gained will be compared in the two arms, as well.

The results and analysis of STIC CTC will be presented by Francois-Clement Bidard, MD, PhD, of Institut Curie, Paris, and the University of Versailles (France), on Thursday, Dec. 6 at 11 a.m. CST.




 

While the majority of the presentations at this year’s San Antonio Breast Cancer Symposium, to be held Dec. 4-8, will focus on treatments, a few will focus on the treatment decisions. One such presentation will report on the findings of the phase 3 STIC CTC trial. This trial seeks to determine if circulating tumor cells (CTC) could serve as a tool to choose between first-line hormone therapy and chemotherapy for ER-positive HER2-negative metastatic breast cancer.

In the standard arm of the trial, treatment was decided by clinicians, taking into account the criteria usually used in this setting. In the CTC arm, the type of treatment was decided by CTC count: Hormone-therapy was chosen if there were fewer than 5 CTC/7.5 mL (CellSearch technique) or chemotherapy if there were 5 or more CTC/7.5 mL. The main objective was to demonstrate the noninferiority of the CTC-based strategy for progression-free survival. The secondary clinical objectives of the French trial were to compare toxicity, quality of life, and overall survival between the two arms. The cost per progression-free life-years gained will be compared in the two arms, as well.

The results and analysis of STIC CTC will be presented by Francois-Clement Bidard, MD, PhD, of Institut Curie, Paris, and the University of Versailles (France), on Thursday, Dec. 6 at 11 a.m. CST.




 

Revisiting the old and enhancing with the new might describe the range of results in HER2+ breast cancer studies to be presented at the upcoming San Antonio Breast Cancer Symposium, which will be held Dec. 4-8 in San Antonio.

Since 2005, 12 months of trastuzumab added to chemotherapy alone has been the standard of care in patients with HER2-positive early breast cancer. PHARE (Protocol for Herceptin as Adjuvant Therapy With Reduced Exposure) was the first trial evaluating a reduced schedule of trastuzumab, a noninferiority trial comparing 6 with 12 months of adjuvant trastuzumab. Results published in 2013 in Lancet Oncology demonstrated a failure to prove that 6 months of treatment was non-inferior to 12 months. The final analysis of PHARE will be presented on Wednesday at SABCS 2018 by Xavier Pivot, MD, PhD, of Paul-Strauss Cancer Centre, Université de Strasbourg (France).

In a more recent study, trastuzumab emtansine (T-DM1) was pitted against trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy including trastuzumab. The primary results of the phase 3 study (KATHERINE) will be presented by Charles E. Geyer, MD, of Virginia Commonwealth University and the Massey Cancer Center, both in Richmond.

As for the new, KATE2 is a phase 2 randomized trial evaluating the addition of checkpoint inhibitor atezolizumab to T-DM1 for patients with locally advanced or metastatic HER2-positive breast cancer who received prior trastuzumab and taxane-based therapy. Results will be presented by Leisha A. Emens, MD, PhD, professor at the University of Pittsburgh and director of translational immunotherapy for the Women’s Cancer Research Center there.




 

Revisiting the old and enhancing with the new might describe the range of results in HER2+ breast cancer studies to be presented at the upcoming San Antonio Breast Cancer Symposium, which will be held Dec. 4-8 in San Antonio.

Since 2005, 12 months of trastuzumab added to chemotherapy alone has been the standard of care in patients with HER2-positive early breast cancer. PHARE (Protocol for Herceptin as Adjuvant Therapy With Reduced Exposure) was the first trial evaluating a reduced schedule of trastuzumab, a noninferiority trial comparing 6 with 12 months of adjuvant trastuzumab. Results published in 2013 in Lancet Oncology demonstrated a failure to prove that 6 months of treatment was non-inferior to 12 months. The final analysis of PHARE will be presented on Wednesday at SABCS 2018 by Xavier Pivot, MD, PhD, of Paul-Strauss Cancer Centre, Université de Strasbourg (France).

In a more recent study, trastuzumab emtansine (T-DM1) was pitted against trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy including trastuzumab. The primary results of the phase 3 study (KATHERINE) will be presented by Charles E. Geyer, MD, of Virginia Commonwealth University and the Massey Cancer Center, both in Richmond.

As for the new, KATE2 is a phase 2 randomized trial evaluating the addition of checkpoint inhibitor atezolizumab to T-DM1 for patients with locally advanced or metastatic HER2-positive breast cancer who received prior trastuzumab and taxane-based therapy. Results will be presented by Leisha A. Emens, MD, PhD, professor at the University of Pittsburgh and director of translational immunotherapy for the Women’s Cancer Research Center there.




 

Revisiting the old and enhancing with the new might describe the range of results in HER2+ breast cancer studies to be presented at the upcoming San Antonio Breast Cancer Symposium, which will be held Dec. 4-8 in San Antonio.

Since 2005, 12 months of trastuzumab added to chemotherapy alone has been the standard of care in patients with HER2-positive early breast cancer. PHARE (Protocol for Herceptin as Adjuvant Therapy With Reduced Exposure) was the first trial evaluating a reduced schedule of trastuzumab, a noninferiority trial comparing 6 with 12 months of adjuvant trastuzumab. Results published in 2013 in Lancet Oncology demonstrated a failure to prove that 6 months of treatment was non-inferior to 12 months. The final analysis of PHARE will be presented on Wednesday at SABCS 2018 by Xavier Pivot, MD, PhD, of Paul-Strauss Cancer Centre, Université de Strasbourg (France).

In a more recent study, trastuzumab emtansine (T-DM1) was pitted against trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy including trastuzumab. The primary results of the phase 3 study (KATHERINE) will be presented by Charles E. Geyer, MD, of Virginia Commonwealth University and the Massey Cancer Center, both in Richmond.

As for the new, KATE2 is a phase 2 randomized trial evaluating the addition of checkpoint inhibitor atezolizumab to T-DM1 for patients with locally advanced or metastatic HER2-positive breast cancer who received prior trastuzumab and taxane-based therapy. Results will be presented by Leisha A. Emens, MD, PhD, professor at the University of Pittsburgh and director of translational immunotherapy for the Women’s Cancer Research Center there.