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No edge for anastrozole over tamoxifen in DCIS
“Our analysis shows that there was really no significant difference in recurrences,” said investigator Ivana Sestak, PhD, of Queen Mary University of London.
Similarly, there were no significant differences in overall deaths or breast cancer deaths. On the other hand, there were “clear differences” in adverse events with the two treatments, Dr. Sestak said.
“[W]e observed an excess of endometrial cancer and ovarian cancers in women who were randomized to tamoxifen and an excess of fractures, strokes, and transient ischemic attacks for women who were randomized to anastrozole,” Dr. Sestak said.
She presented these results at the 2020 San Antonio Breast Cancer Symposium.
Comparing IBIS-II DCIS with prior results
“The long-term results of the IBIS-II [DCIS] trial are consistent with previous results,” said Halle Moore, MD, of the Cleveland Clinic, who was not involved in this study.
However, the results do contrast with the findings of the NSABP-B35 study, “which demonstrated a very modest advantage to anastrozole that was mostly limited to younger postmenopausal women,” she said.
Indeed, a significant 27% reduction in recurrence was seen with anastrozole, compared with tamoxifen at a median of 9 years of follow-up in the NSABP-B35 study. But, as Dr. Sestak pointed out, that reduction “was mainly observed during the posttreatment follow-up period and not during the active treatment period.”
In the IBIS-II DCIS study, there was a nonsignificant 11% reduction in breast cancer recurrence with anastrozole.
The investigators did examine the potential effect of age on the rate of breast cancer recurrence, but no significant differences were found. They also looked at the active and post–endocrine therapy treatment periods, all showing no benefit of one drug over the other.
“So we clearly cannot replicate the findings of the NSABP-B35 study,” Dr. Sestak acknowledged.
IBIS-II DCIS details and results
Aromatase inhibitors such as anastrozole have been shown to be more effective than tamoxifen for preventing recurrence in postmenopausal HR+ women with invasive breast cancer, but it wasn’t previously known if this included women with HR-positive DCIS.
The IBIS-II DCIS study was therefore designed to determine if there was any advantage of anastrazole over tamoxifen. The phase 3 trial enrolled 2,980 postmenopausal women with HR-positive DCIS. They were randomized to 5 years of anastrozole or 5 years of tamoxifen.
“Women were followed up during this active period of treatment by clinic visits,” explained Dr. Sestak. “Thereafter, we collected data via questionnaire, registry data sets, and clinic visits.”
Baseline characteristics were similar between the treatment arms. The median age was about 60 years in both arms. Similar proportions of patients had received hormone replacement therapy (44.2% in the tamoxifen arm and 46.8% in the anastrozole arm) or undergone radiotherapy (71.5% and 70.9%, respectively).
Results showed little difference in breast cancer recurrence rates. At a median follow-up of 11.6 years, the rate of recurrence was 9.7% with tamoxifen and 8.5% with anastrozole (hazard ratio, 0.89; P = .401).
Trends were seen favoring anastrozole in estrogen receptor–positive and HER2-negative women, but this was only while women were being actively treated.
Death rates were similar – 4.2% with anastrozole and 4.5% with tamoxifen (odds ratio, 0.93). There were three breast cancer deaths in each treatment arm.
Adverse events could be the deciding factor
“The main take-away from this presentation is that choice of adjuvant endocrine therapy for DCIS should be individualized based primarily on the different side effect profiles of the two medications,” Dr. Moore said.
During the trial, “a significant 34% increase in fractures was observed in women who received anastrozole, compared to tamoxifen [HR, 1.34; P = .013],” Dr. Sestak said.
“We also observed a threefold increase in strokes and transient ischemic attacks with anastrozole, compared to tamoxifen [HR, 3.10; P = .021 for both strokes and transient ischemic attacks],” Dr. Sestak added.
She acknowledged that this finding is inconsistent with what is known about aromatase inhibitors in general. It could be that, rather than anastrozole raising the risk of strokes and transient ischemic attacks, tamoxifen was having a beneficial effect. This could be a result of tamoxifen improving endothelial function by increasing vasodilation, “but it is really not clear what the mechanism is,” Dr. Sestak said.
Also contrary to what is known about tamoxifen was an excess of deaths because of endometrial cancer or ovarian cancers. Wherever possible, the pathology reports had been requested to confirm the cause of death, “so we are pretty sure that they are true ovarian cancers and not some other abdominal tumors,” Dr. Sestak said.
“We did observe very clear differences in terms of adverse events,” she said, adding that “improved understanding of adverse event profiles will help patients with HR-positive DCIS to make an informed decision regarding their treatment.”
The IBIS-II DCIS trial was funded by Cancer Research UK, the National Health and Medical Research Council Australia, Breast Cancer Research Foundation, AstraZeneca, and Sanofi Aventis. Two investigators disclosed relationships with AstraZeneca, and one disclosed a relationship with Cancer Research UK. Dr. Sestak and Dr. Moore had no relevant disclosures.
SOURCE: Sestak I et al. SABCS 2020, Abstract GS2-02.
“Our analysis shows that there was really no significant difference in recurrences,” said investigator Ivana Sestak, PhD, of Queen Mary University of London.
Similarly, there were no significant differences in overall deaths or breast cancer deaths. On the other hand, there were “clear differences” in adverse events with the two treatments, Dr. Sestak said.
“[W]e observed an excess of endometrial cancer and ovarian cancers in women who were randomized to tamoxifen and an excess of fractures, strokes, and transient ischemic attacks for women who were randomized to anastrozole,” Dr. Sestak said.
She presented these results at the 2020 San Antonio Breast Cancer Symposium.
Comparing IBIS-II DCIS with prior results
“The long-term results of the IBIS-II [DCIS] trial are consistent with previous results,” said Halle Moore, MD, of the Cleveland Clinic, who was not involved in this study.
However, the results do contrast with the findings of the NSABP-B35 study, “which demonstrated a very modest advantage to anastrozole that was mostly limited to younger postmenopausal women,” she said.
Indeed, a significant 27% reduction in recurrence was seen with anastrozole, compared with tamoxifen at a median of 9 years of follow-up in the NSABP-B35 study. But, as Dr. Sestak pointed out, that reduction “was mainly observed during the posttreatment follow-up period and not during the active treatment period.”
In the IBIS-II DCIS study, there was a nonsignificant 11% reduction in breast cancer recurrence with anastrozole.
The investigators did examine the potential effect of age on the rate of breast cancer recurrence, but no significant differences were found. They also looked at the active and post–endocrine therapy treatment periods, all showing no benefit of one drug over the other.
“So we clearly cannot replicate the findings of the NSABP-B35 study,” Dr. Sestak acknowledged.
IBIS-II DCIS details and results
Aromatase inhibitors such as anastrozole have been shown to be more effective than tamoxifen for preventing recurrence in postmenopausal HR+ women with invasive breast cancer, but it wasn’t previously known if this included women with HR-positive DCIS.
The IBIS-II DCIS study was therefore designed to determine if there was any advantage of anastrazole over tamoxifen. The phase 3 trial enrolled 2,980 postmenopausal women with HR-positive DCIS. They were randomized to 5 years of anastrozole or 5 years of tamoxifen.
“Women were followed up during this active period of treatment by clinic visits,” explained Dr. Sestak. “Thereafter, we collected data via questionnaire, registry data sets, and clinic visits.”
Baseline characteristics were similar between the treatment arms. The median age was about 60 years in both arms. Similar proportions of patients had received hormone replacement therapy (44.2% in the tamoxifen arm and 46.8% in the anastrozole arm) or undergone radiotherapy (71.5% and 70.9%, respectively).
Results showed little difference in breast cancer recurrence rates. At a median follow-up of 11.6 years, the rate of recurrence was 9.7% with tamoxifen and 8.5% with anastrozole (hazard ratio, 0.89; P = .401).
Trends were seen favoring anastrozole in estrogen receptor–positive and HER2-negative women, but this was only while women were being actively treated.
Death rates were similar – 4.2% with anastrozole and 4.5% with tamoxifen (odds ratio, 0.93). There were three breast cancer deaths in each treatment arm.
Adverse events could be the deciding factor
“The main take-away from this presentation is that choice of adjuvant endocrine therapy for DCIS should be individualized based primarily on the different side effect profiles of the two medications,” Dr. Moore said.
During the trial, “a significant 34% increase in fractures was observed in women who received anastrozole, compared to tamoxifen [HR, 1.34; P = .013],” Dr. Sestak said.
“We also observed a threefold increase in strokes and transient ischemic attacks with anastrozole, compared to tamoxifen [HR, 3.10; P = .021 for both strokes and transient ischemic attacks],” Dr. Sestak added.
She acknowledged that this finding is inconsistent with what is known about aromatase inhibitors in general. It could be that, rather than anastrozole raising the risk of strokes and transient ischemic attacks, tamoxifen was having a beneficial effect. This could be a result of tamoxifen improving endothelial function by increasing vasodilation, “but it is really not clear what the mechanism is,” Dr. Sestak said.
Also contrary to what is known about tamoxifen was an excess of deaths because of endometrial cancer or ovarian cancers. Wherever possible, the pathology reports had been requested to confirm the cause of death, “so we are pretty sure that they are true ovarian cancers and not some other abdominal tumors,” Dr. Sestak said.
“We did observe very clear differences in terms of adverse events,” she said, adding that “improved understanding of adverse event profiles will help patients with HR-positive DCIS to make an informed decision regarding their treatment.”
The IBIS-II DCIS trial was funded by Cancer Research UK, the National Health and Medical Research Council Australia, Breast Cancer Research Foundation, AstraZeneca, and Sanofi Aventis. Two investigators disclosed relationships with AstraZeneca, and one disclosed a relationship with Cancer Research UK. Dr. Sestak and Dr. Moore had no relevant disclosures.
SOURCE: Sestak I et al. SABCS 2020, Abstract GS2-02.
“Our analysis shows that there was really no significant difference in recurrences,” said investigator Ivana Sestak, PhD, of Queen Mary University of London.
Similarly, there were no significant differences in overall deaths or breast cancer deaths. On the other hand, there were “clear differences” in adverse events with the two treatments, Dr. Sestak said.
“[W]e observed an excess of endometrial cancer and ovarian cancers in women who were randomized to tamoxifen and an excess of fractures, strokes, and transient ischemic attacks for women who were randomized to anastrozole,” Dr. Sestak said.
She presented these results at the 2020 San Antonio Breast Cancer Symposium.
Comparing IBIS-II DCIS with prior results
“The long-term results of the IBIS-II [DCIS] trial are consistent with previous results,” said Halle Moore, MD, of the Cleveland Clinic, who was not involved in this study.
However, the results do contrast with the findings of the NSABP-B35 study, “which demonstrated a very modest advantage to anastrozole that was mostly limited to younger postmenopausal women,” she said.
Indeed, a significant 27% reduction in recurrence was seen with anastrozole, compared with tamoxifen at a median of 9 years of follow-up in the NSABP-B35 study. But, as Dr. Sestak pointed out, that reduction “was mainly observed during the posttreatment follow-up period and not during the active treatment period.”
In the IBIS-II DCIS study, there was a nonsignificant 11% reduction in breast cancer recurrence with anastrozole.
The investigators did examine the potential effect of age on the rate of breast cancer recurrence, but no significant differences were found. They also looked at the active and post–endocrine therapy treatment periods, all showing no benefit of one drug over the other.
“So we clearly cannot replicate the findings of the NSABP-B35 study,” Dr. Sestak acknowledged.
IBIS-II DCIS details and results
Aromatase inhibitors such as anastrozole have been shown to be more effective than tamoxifen for preventing recurrence in postmenopausal HR+ women with invasive breast cancer, but it wasn’t previously known if this included women with HR-positive DCIS.
The IBIS-II DCIS study was therefore designed to determine if there was any advantage of anastrazole over tamoxifen. The phase 3 trial enrolled 2,980 postmenopausal women with HR-positive DCIS. They were randomized to 5 years of anastrozole or 5 years of tamoxifen.
“Women were followed up during this active period of treatment by clinic visits,” explained Dr. Sestak. “Thereafter, we collected data via questionnaire, registry data sets, and clinic visits.”
Baseline characteristics were similar between the treatment arms. The median age was about 60 years in both arms. Similar proportions of patients had received hormone replacement therapy (44.2% in the tamoxifen arm and 46.8% in the anastrozole arm) or undergone radiotherapy (71.5% and 70.9%, respectively).
Results showed little difference in breast cancer recurrence rates. At a median follow-up of 11.6 years, the rate of recurrence was 9.7% with tamoxifen and 8.5% with anastrozole (hazard ratio, 0.89; P = .401).
Trends were seen favoring anastrozole in estrogen receptor–positive and HER2-negative women, but this was only while women were being actively treated.
Death rates were similar – 4.2% with anastrozole and 4.5% with tamoxifen (odds ratio, 0.93). There were three breast cancer deaths in each treatment arm.
Adverse events could be the deciding factor
“The main take-away from this presentation is that choice of adjuvant endocrine therapy for DCIS should be individualized based primarily on the different side effect profiles of the two medications,” Dr. Moore said.
During the trial, “a significant 34% increase in fractures was observed in women who received anastrozole, compared to tamoxifen [HR, 1.34; P = .013],” Dr. Sestak said.
“We also observed a threefold increase in strokes and transient ischemic attacks with anastrozole, compared to tamoxifen [HR, 3.10; P = .021 for both strokes and transient ischemic attacks],” Dr. Sestak added.
She acknowledged that this finding is inconsistent with what is known about aromatase inhibitors in general. It could be that, rather than anastrozole raising the risk of strokes and transient ischemic attacks, tamoxifen was having a beneficial effect. This could be a result of tamoxifen improving endothelial function by increasing vasodilation, “but it is really not clear what the mechanism is,” Dr. Sestak said.
Also contrary to what is known about tamoxifen was an excess of deaths because of endometrial cancer or ovarian cancers. Wherever possible, the pathology reports had been requested to confirm the cause of death, “so we are pretty sure that they are true ovarian cancers and not some other abdominal tumors,” Dr. Sestak said.
“We did observe very clear differences in terms of adverse events,” she said, adding that “improved understanding of adverse event profiles will help patients with HR-positive DCIS to make an informed decision regarding their treatment.”
The IBIS-II DCIS trial was funded by Cancer Research UK, the National Health and Medical Research Council Australia, Breast Cancer Research Foundation, AstraZeneca, and Sanofi Aventis. Two investigators disclosed relationships with AstraZeneca, and one disclosed a relationship with Cancer Research UK. Dr. Sestak and Dr. Moore had no relevant disclosures.
SOURCE: Sestak I et al. SABCS 2020, Abstract GS2-02.
FROM SABCS 2020
Reproductive Rounds: Fertility preservation options for cancer patients
What is more stressful in the mind of a patient – a diagnosis of cancer or infertility? An infertile woman’s anxiety and depression scores are equivalent to one with cancer (J Psychosom Obstet Gynecol. 1993;14 Suppl:45-52). These two diseases intersect in the burgeoning field of oncofertility, the collaboration of oncology with reproductive endocrinology to offer patients the option of fertility preservation. The term oncofertility was first coined by Teresa Woodruff, PhD, in 2005 during her invited lecture at the University of Calgary symposium called “Pushing the Boundaries – Advances that Will Change the World in 20 Years.” Her prediction has reached its fruition. This article will review fertility preservation options for female oncology patients.
The ability for oncofertility to exist is the result of improved cancer survival rates and advances in reproductive medicine. Improvements in the treatment of cancer enable many young women to survive and focus on the potential of having a family. Malignancies striking young people, particularly breast, lymphoma, and melanoma, have encouraging 5-year survival rates. If invasive cancer is located only in the breast (affecting 62% of women diagnosed), the 5-year survival rate is 99%. For all with Hodgkin lymphoma, the 5-year survival is 87%, increasing to 92% if the cancer is found in its earliest stages. Among all people with melanoma of the skin, from the time of initial diagnosis, the 5-year survival is 92%.
Long-term survival is expected for 80% of children and adolescents diagnosed with cancer (Obstet Gynecol. 2010;116: 1171-83).
Iatrogenic effects
The reproductive risk of cancer treatment is gonadotoxicity and the subsequent iatrogenic primary ovarian insufficiency (POI, prior termed premature ovarian failure) or infertility.
Chemotherapy with alkylating agents, such as cyclophosphamide, is associated with the greatest chance of amenorrhea (Breast Cancer Res Treat. 2014;145:113-28). Chemotherapy with cyclophosphamide, methotrexate, and 5 fluorouracil (CMF – commonly used for the treatment of breast cancer) will usually result in loss of ovarian function in 33% of women under age 30, 50% of women aged 30-35, 75% of women aged 35-40, and 95% of women over age 40 (J Clin Oncol. 2006;24:5769-79).
The dose at which 50% of oocytes are lost due to radiation is under 2 Gy (Hum Reprod. 2003;18:117-21). Unfortunately, the minimum dose decreases with advancing age of the woman, contributed by natural diminishing reserve and an increase in radiosensitivity of oocytes. Age, proximity of the radiation field to the ovaries, and total dose are important factors determining risk of POI. For brain tumors, cranial irradiation may result in hypothalamic amenorrhea.
Protection
The use of GnRH agonist for 6 months during chemotherapy has been controversial with mixed results in avoiding ovarian failure. A recent study suggests a GnRH agonist does reduce the prevalence of POI (J Clin Oncol. 2018;36:1981-90) in women treated for breast cancer but the subsequent ovarian reserve is low (Ann Oncol. 2017;28:1811-6). There are not enough data now to consider this the sole viable option for all patients to preserve fertility.
Patients requiring local pelvic radiation treatment may benefit from transposition of the ovaries to sites away from maximal radiation exposure.
Oocyte cryopreservation (OC) and ovarian tissue cryopreservation (OTC)
Since 2012, the American Society for Reproductive Medicine lifted the experimental designation on OC and, last year, the society removed the same label for OTC, providing an additional fertility preservation option.
Ovarian stimulation and egg retrieval for OC can now occur literally within 2 weeks because of a random start protocol whereby women are stimulated any day in their cycle, pre- and post ovulation. Studies have shown equivalent yield of oocytes.
OC followed by thawing for subsequent fertilization and embryo transfer is employed as a routine matter with egg donation cycles. While there remains debate over whether live birth rates using frozen eggs are inferior to fresh eggs, a learning curve with the new technology may be the important factor (Obstet Gynecol. 2020;135:709-16).
When urgent cancer treatment precludes ovarian stimulation for OC, then OTC is a viable option. Another population that could benefit from OTC are prepubertal girls facing gonadotoxic therapy. More research is required to determine the quality of eggs obtained through ovarian stimulation in adolescent and young adult patients. While leukemic patients are eligible for OTC, there is concern about reseeding malignant cells with future autologous transplantation of tissue.
OTC involves obtaining ovarian cortical tissue, dissecting the tissue into small fragments, and cryopreserving it using either a slow-cool technique or vitrification. Orthotopic transplantation has been the most successful method for using ovarian tissue in humans. To date, live birth rates are modest (Fertil Steril. 2015;104:1097-8).
Recent research has combined the freezing of both mature and immature eggs, the latter undergoing IVM (in-vitro maturation) to maximize the potential for fertilizable eggs. Women with polycystic ovary syndrome and certain cancers or medical conditions that warrant avoiding supraphysiologic levels of estradiol from ovarian stimulation, may benefit from the retrieval of immature eggs from unstimulated ovaries.
Pregnancy outcomes using embryos created from ovaries recently exposed to chemotherapy in humans are not known but animal studies suggest there may be higher rates of miscarriage and birth defects.
Breast cancer – a special scenario
With every breast cancer patient, I review the theoretical concern over increasing estradiol levels during an IVF stimulation cycle with the potential impact on her cancer prognosis. Fortunately, the literature has not demonstrated an increased risk of breast cancer or recurrence after undergoing an IVF cycle. Currently, the use of aromatase inhibitors with gonadotropins along with a GnRH-antagonist is the protocol to maintain a lower estradiol level during stimulation, which may be of benefit for breast cancer prognosis. The use of aromatase inhibitors is an off-label indication for fertility with no definitive evidence of teratogenicity. Preimplantation genetic testing of embryos is available and approved by the American Society for Reproductive Medicine for BRCA gene mutation patients.
Oncofertility is an exciting field to allow cancer survivors the option for a biological child. We recommend all our cancer patients meet with our reproductive psychologist to assist in coping with the overwhelming information presented in a short time frame.
Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and associate professor of obstetrics and gynecology at the University of Central Florida, Orlando.
What is more stressful in the mind of a patient – a diagnosis of cancer or infertility? An infertile woman’s anxiety and depression scores are equivalent to one with cancer (J Psychosom Obstet Gynecol. 1993;14 Suppl:45-52). These two diseases intersect in the burgeoning field of oncofertility, the collaboration of oncology with reproductive endocrinology to offer patients the option of fertility preservation. The term oncofertility was first coined by Teresa Woodruff, PhD, in 2005 during her invited lecture at the University of Calgary symposium called “Pushing the Boundaries – Advances that Will Change the World in 20 Years.” Her prediction has reached its fruition. This article will review fertility preservation options for female oncology patients.
The ability for oncofertility to exist is the result of improved cancer survival rates and advances in reproductive medicine. Improvements in the treatment of cancer enable many young women to survive and focus on the potential of having a family. Malignancies striking young people, particularly breast, lymphoma, and melanoma, have encouraging 5-year survival rates. If invasive cancer is located only in the breast (affecting 62% of women diagnosed), the 5-year survival rate is 99%. For all with Hodgkin lymphoma, the 5-year survival is 87%, increasing to 92% if the cancer is found in its earliest stages. Among all people with melanoma of the skin, from the time of initial diagnosis, the 5-year survival is 92%.
Long-term survival is expected for 80% of children and adolescents diagnosed with cancer (Obstet Gynecol. 2010;116: 1171-83).
Iatrogenic effects
The reproductive risk of cancer treatment is gonadotoxicity and the subsequent iatrogenic primary ovarian insufficiency (POI, prior termed premature ovarian failure) or infertility.
Chemotherapy with alkylating agents, such as cyclophosphamide, is associated with the greatest chance of amenorrhea (Breast Cancer Res Treat. 2014;145:113-28). Chemotherapy with cyclophosphamide, methotrexate, and 5 fluorouracil (CMF – commonly used for the treatment of breast cancer) will usually result in loss of ovarian function in 33% of women under age 30, 50% of women aged 30-35, 75% of women aged 35-40, and 95% of women over age 40 (J Clin Oncol. 2006;24:5769-79).
The dose at which 50% of oocytes are lost due to radiation is under 2 Gy (Hum Reprod. 2003;18:117-21). Unfortunately, the minimum dose decreases with advancing age of the woman, contributed by natural diminishing reserve and an increase in radiosensitivity of oocytes. Age, proximity of the radiation field to the ovaries, and total dose are important factors determining risk of POI. For brain tumors, cranial irradiation may result in hypothalamic amenorrhea.
Protection
The use of GnRH agonist for 6 months during chemotherapy has been controversial with mixed results in avoiding ovarian failure. A recent study suggests a GnRH agonist does reduce the prevalence of POI (J Clin Oncol. 2018;36:1981-90) in women treated for breast cancer but the subsequent ovarian reserve is low (Ann Oncol. 2017;28:1811-6). There are not enough data now to consider this the sole viable option for all patients to preserve fertility.
Patients requiring local pelvic radiation treatment may benefit from transposition of the ovaries to sites away from maximal radiation exposure.
Oocyte cryopreservation (OC) and ovarian tissue cryopreservation (OTC)
Since 2012, the American Society for Reproductive Medicine lifted the experimental designation on OC and, last year, the society removed the same label for OTC, providing an additional fertility preservation option.
Ovarian stimulation and egg retrieval for OC can now occur literally within 2 weeks because of a random start protocol whereby women are stimulated any day in their cycle, pre- and post ovulation. Studies have shown equivalent yield of oocytes.
OC followed by thawing for subsequent fertilization and embryo transfer is employed as a routine matter with egg donation cycles. While there remains debate over whether live birth rates using frozen eggs are inferior to fresh eggs, a learning curve with the new technology may be the important factor (Obstet Gynecol. 2020;135:709-16).
When urgent cancer treatment precludes ovarian stimulation for OC, then OTC is a viable option. Another population that could benefit from OTC are prepubertal girls facing gonadotoxic therapy. More research is required to determine the quality of eggs obtained through ovarian stimulation in adolescent and young adult patients. While leukemic patients are eligible for OTC, there is concern about reseeding malignant cells with future autologous transplantation of tissue.
OTC involves obtaining ovarian cortical tissue, dissecting the tissue into small fragments, and cryopreserving it using either a slow-cool technique or vitrification. Orthotopic transplantation has been the most successful method for using ovarian tissue in humans. To date, live birth rates are modest (Fertil Steril. 2015;104:1097-8).
Recent research has combined the freezing of both mature and immature eggs, the latter undergoing IVM (in-vitro maturation) to maximize the potential for fertilizable eggs. Women with polycystic ovary syndrome and certain cancers or medical conditions that warrant avoiding supraphysiologic levels of estradiol from ovarian stimulation, may benefit from the retrieval of immature eggs from unstimulated ovaries.
Pregnancy outcomes using embryos created from ovaries recently exposed to chemotherapy in humans are not known but animal studies suggest there may be higher rates of miscarriage and birth defects.
Breast cancer – a special scenario
With every breast cancer patient, I review the theoretical concern over increasing estradiol levels during an IVF stimulation cycle with the potential impact on her cancer prognosis. Fortunately, the literature has not demonstrated an increased risk of breast cancer or recurrence after undergoing an IVF cycle. Currently, the use of aromatase inhibitors with gonadotropins along with a GnRH-antagonist is the protocol to maintain a lower estradiol level during stimulation, which may be of benefit for breast cancer prognosis. The use of aromatase inhibitors is an off-label indication for fertility with no definitive evidence of teratogenicity. Preimplantation genetic testing of embryos is available and approved by the American Society for Reproductive Medicine for BRCA gene mutation patients.
Oncofertility is an exciting field to allow cancer survivors the option for a biological child. We recommend all our cancer patients meet with our reproductive psychologist to assist in coping with the overwhelming information presented in a short time frame.
Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and associate professor of obstetrics and gynecology at the University of Central Florida, Orlando.
What is more stressful in the mind of a patient – a diagnosis of cancer or infertility? An infertile woman’s anxiety and depression scores are equivalent to one with cancer (J Psychosom Obstet Gynecol. 1993;14 Suppl:45-52). These two diseases intersect in the burgeoning field of oncofertility, the collaboration of oncology with reproductive endocrinology to offer patients the option of fertility preservation. The term oncofertility was first coined by Teresa Woodruff, PhD, in 2005 during her invited lecture at the University of Calgary symposium called “Pushing the Boundaries – Advances that Will Change the World in 20 Years.” Her prediction has reached its fruition. This article will review fertility preservation options for female oncology patients.
The ability for oncofertility to exist is the result of improved cancer survival rates and advances in reproductive medicine. Improvements in the treatment of cancer enable many young women to survive and focus on the potential of having a family. Malignancies striking young people, particularly breast, lymphoma, and melanoma, have encouraging 5-year survival rates. If invasive cancer is located only in the breast (affecting 62% of women diagnosed), the 5-year survival rate is 99%. For all with Hodgkin lymphoma, the 5-year survival is 87%, increasing to 92% if the cancer is found in its earliest stages. Among all people with melanoma of the skin, from the time of initial diagnosis, the 5-year survival is 92%.
Long-term survival is expected for 80% of children and adolescents diagnosed with cancer (Obstet Gynecol. 2010;116: 1171-83).
Iatrogenic effects
The reproductive risk of cancer treatment is gonadotoxicity and the subsequent iatrogenic primary ovarian insufficiency (POI, prior termed premature ovarian failure) or infertility.
Chemotherapy with alkylating agents, such as cyclophosphamide, is associated with the greatest chance of amenorrhea (Breast Cancer Res Treat. 2014;145:113-28). Chemotherapy with cyclophosphamide, methotrexate, and 5 fluorouracil (CMF – commonly used for the treatment of breast cancer) will usually result in loss of ovarian function in 33% of women under age 30, 50% of women aged 30-35, 75% of women aged 35-40, and 95% of women over age 40 (J Clin Oncol. 2006;24:5769-79).
The dose at which 50% of oocytes are lost due to radiation is under 2 Gy (Hum Reprod. 2003;18:117-21). Unfortunately, the minimum dose decreases with advancing age of the woman, contributed by natural diminishing reserve and an increase in radiosensitivity of oocytes. Age, proximity of the radiation field to the ovaries, and total dose are important factors determining risk of POI. For brain tumors, cranial irradiation may result in hypothalamic amenorrhea.
Protection
The use of GnRH agonist for 6 months during chemotherapy has been controversial with mixed results in avoiding ovarian failure. A recent study suggests a GnRH agonist does reduce the prevalence of POI (J Clin Oncol. 2018;36:1981-90) in women treated for breast cancer but the subsequent ovarian reserve is low (Ann Oncol. 2017;28:1811-6). There are not enough data now to consider this the sole viable option for all patients to preserve fertility.
Patients requiring local pelvic radiation treatment may benefit from transposition of the ovaries to sites away from maximal radiation exposure.
Oocyte cryopreservation (OC) and ovarian tissue cryopreservation (OTC)
Since 2012, the American Society for Reproductive Medicine lifted the experimental designation on OC and, last year, the society removed the same label for OTC, providing an additional fertility preservation option.
Ovarian stimulation and egg retrieval for OC can now occur literally within 2 weeks because of a random start protocol whereby women are stimulated any day in their cycle, pre- and post ovulation. Studies have shown equivalent yield of oocytes.
OC followed by thawing for subsequent fertilization and embryo transfer is employed as a routine matter with egg donation cycles. While there remains debate over whether live birth rates using frozen eggs are inferior to fresh eggs, a learning curve with the new technology may be the important factor (Obstet Gynecol. 2020;135:709-16).
When urgent cancer treatment precludes ovarian stimulation for OC, then OTC is a viable option. Another population that could benefit from OTC are prepubertal girls facing gonadotoxic therapy. More research is required to determine the quality of eggs obtained through ovarian stimulation in adolescent and young adult patients. While leukemic patients are eligible for OTC, there is concern about reseeding malignant cells with future autologous transplantation of tissue.
OTC involves obtaining ovarian cortical tissue, dissecting the tissue into small fragments, and cryopreserving it using either a slow-cool technique or vitrification. Orthotopic transplantation has been the most successful method for using ovarian tissue in humans. To date, live birth rates are modest (Fertil Steril. 2015;104:1097-8).
Recent research has combined the freezing of both mature and immature eggs, the latter undergoing IVM (in-vitro maturation) to maximize the potential for fertilizable eggs. Women with polycystic ovary syndrome and certain cancers or medical conditions that warrant avoiding supraphysiologic levels of estradiol from ovarian stimulation, may benefit from the retrieval of immature eggs from unstimulated ovaries.
Pregnancy outcomes using embryos created from ovaries recently exposed to chemotherapy in humans are not known but animal studies suggest there may be higher rates of miscarriage and birth defects.
Breast cancer – a special scenario
With every breast cancer patient, I review the theoretical concern over increasing estradiol levels during an IVF stimulation cycle with the potential impact on her cancer prognosis. Fortunately, the literature has not demonstrated an increased risk of breast cancer or recurrence after undergoing an IVF cycle. Currently, the use of aromatase inhibitors with gonadotropins along with a GnRH-antagonist is the protocol to maintain a lower estradiol level during stimulation, which may be of benefit for breast cancer prognosis. The use of aromatase inhibitors is an off-label indication for fertility with no definitive evidence of teratogenicity. Preimplantation genetic testing of embryos is available and approved by the American Society for Reproductive Medicine for BRCA gene mutation patients.
Oncofertility is an exciting field to allow cancer survivors the option for a biological child. We recommend all our cancer patients meet with our reproductive psychologist to assist in coping with the overwhelming information presented in a short time frame.
Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and associate professor of obstetrics and gynecology at the University of Central Florida, Orlando.
Long-term APBI cosmetic, toxicity data reported
Long-term cosmetic and toxicity outcomes are good for both accelerated partial breast irradiation (APBI) delivered with 3D-conformal radiotherapy and whole-breast irradiation (WBI), with the latter having a slight edge, the IRMA trial shows.
Findings were reported at the European Society for Radiology and Oncology 2020 Online Congress by Bruno Meduri, MD, a radiation oncologist at University Hospital of Modena, Italy.
Uptake of APBI has increased since it was approved nearly 2 decades ago. However, its long-term outcomes are still being parsed, and issues such as appropriate patient selection and optimal delivery technique are still being clarified (Curr Breast Cancer Rep. 2020;18:1-10).
IRMA is a European, multicenter, phase 3 randomized controlled trial conducted among 3,279 women aged 49 years and older who underwent breast-conserving surgery for early-stage breast cancer (measuring <3 cm in diameter, and pathologic N0 or N1) with negative resection margins.
The women were randomized to APBI using 3D-conformal radiotherapy (38.5 Gy in 10 fractions, twice daily) or conventional or hypofractionated WBI (50.0 Gy in 25 fractions, once daily). All additionally received adjuvant therapy according to institutional guidelines.
Patients and physicians separately rated cosmetic outcomes on a 4-point scale using the untreated breast as a reference, and toxicity was graded with the Radiation Therapy Oncology Group (RTOG) scale.
Over a median follow-up of 5 years, patients rated cosmesis more favorably than physicians did at all time points, and there was a trend toward slight worsening of cosmesis in the APBI group with time, Dr. Meduri reported.
At 1 year, cosmesis did not differ significantly between treatment groups regardless of the rater. But compared with the WBI group, the APBI group more often had patient-rated fair to poor cosmesis at 3 years (12.7% vs. 9.4%; P =.02) and at 5 years (15.0% vs. 10.1%; P = .007), as well as physician-rated fair to poor cosmesis at 3 years (18.0% vs. 13.1%; P = .003) and at 5 years (18.4% vs. 14.2%; P = .04).
Women treated with APBI had less acute skin toxicity (P < .001), with 4.9% developing grade 2 toxicity, compared with 21.4% of peers treated with WBI. Late skin toxicity was also less common in the APBI group overall (P < .001), but the rate of grade 3 or 4 late skin toxicity was similar.
On the other hand, the APBI group had more late bone toxicity overall (P < .001) and late bone toxicity of grade 3 or 4 (1.0% vs. 0%; P < .05), as well as more late soft tissue (subcutaneous) toxicity overall (P < .001) and late soft tissue toxicity of grade 3 or 4 (2.6% vs. 1.1%; P < .05).
The two groups had essentially the same late lung toxicity.
Women treated with APBI had higher 5-year cumulative incidences of soft tissue toxicity of grade 2 or worse (29.7% vs. 17.9%; P < .0001) and grade 3 or worse (2.6% vs. 1.1%; P = .0016). Cumulative incidences of skin toxicity of these grades did not differ significantly.
Importantly, the prevalences of late soft tissue and skin toxicity at 5 years were much lower than the cumulative incidences, Dr. Meduri noted. “This means that the side effects in some patients tend to resolve over time.”
Although the prevalence of grade 2-4 skin toxicity increased slightly at 3 years and 5 years in both groups, the prevalence of grade 2-4 soft tissue toxicity was stable.
Finally, the volume that received at least 38.5 Gy of radiation was higher for patients who developed late grade 3 or 4 bone toxicity than for those who did not (2.1 vs. 0.82 cc; P = .027), whereas other dosimetric parameters were similar.
“The toxicity of the whole cohort was very low,” Dr. Meduri summarized. “APBI was associated with a slightly higher rate of late soft tissue and bone toxicity, with a slight decrease in cosmetic outcome at 5 years. But longer follow-up is needed to confirm these results.”
The IRMA findings confirm previous results from the RAPID trial showing that APBI delivered via 3D-conformal radiotherapy may be associated with increased rates of toxicity, Chirag Shah, MD, a radiation oncologist at the Cleveland Clinic in Ohio, said in an interview.
“While cancer control outcomes were not presented, the toxicity outcomes are important and validate why many are moving away from 3D-conformal radiotherapy APBI,” he elaborated. “We are seeing increased use of APBI in some centers in the U.S., though there has been a greater shift to IMRT [intensity-modulated radiation therapy] based on 10-year data from the Florence randomized trial, which showed reduced side effects.”
“I think the results of this study are practice-confirming,” Dr. Shah concluded. “Moving forward, shorter APBI schedules will be considered as we now have 5-fraction whole-breast regimens available, as assessed in the FAST and FAST-Forward trials.”
Dr. Meduri disclosed expert board service for MSD, and financial support for attending congresses from Ipsen, AstraZeneca, and Merck. The trial was sponsored by Regione Emilia-Romagna. Dr. Shah disclosed consulting for Impedimed and PreludeDX, and receiving grants from Varian, VisionRT, and PreludeDX.
SOURCE: Meduri B et al. ESTRO 2020. Abstract OC-0611.
Long-term cosmetic and toxicity outcomes are good for both accelerated partial breast irradiation (APBI) delivered with 3D-conformal radiotherapy and whole-breast irradiation (WBI), with the latter having a slight edge, the IRMA trial shows.
Findings were reported at the European Society for Radiology and Oncology 2020 Online Congress by Bruno Meduri, MD, a radiation oncologist at University Hospital of Modena, Italy.
Uptake of APBI has increased since it was approved nearly 2 decades ago. However, its long-term outcomes are still being parsed, and issues such as appropriate patient selection and optimal delivery technique are still being clarified (Curr Breast Cancer Rep. 2020;18:1-10).
IRMA is a European, multicenter, phase 3 randomized controlled trial conducted among 3,279 women aged 49 years and older who underwent breast-conserving surgery for early-stage breast cancer (measuring <3 cm in diameter, and pathologic N0 or N1) with negative resection margins.
The women were randomized to APBI using 3D-conformal radiotherapy (38.5 Gy in 10 fractions, twice daily) or conventional or hypofractionated WBI (50.0 Gy in 25 fractions, once daily). All additionally received adjuvant therapy according to institutional guidelines.
Patients and physicians separately rated cosmetic outcomes on a 4-point scale using the untreated breast as a reference, and toxicity was graded with the Radiation Therapy Oncology Group (RTOG) scale.
Over a median follow-up of 5 years, patients rated cosmesis more favorably than physicians did at all time points, and there was a trend toward slight worsening of cosmesis in the APBI group with time, Dr. Meduri reported.
At 1 year, cosmesis did not differ significantly between treatment groups regardless of the rater. But compared with the WBI group, the APBI group more often had patient-rated fair to poor cosmesis at 3 years (12.7% vs. 9.4%; P =.02) and at 5 years (15.0% vs. 10.1%; P = .007), as well as physician-rated fair to poor cosmesis at 3 years (18.0% vs. 13.1%; P = .003) and at 5 years (18.4% vs. 14.2%; P = .04).
Women treated with APBI had less acute skin toxicity (P < .001), with 4.9% developing grade 2 toxicity, compared with 21.4% of peers treated with WBI. Late skin toxicity was also less common in the APBI group overall (P < .001), but the rate of grade 3 or 4 late skin toxicity was similar.
On the other hand, the APBI group had more late bone toxicity overall (P < .001) and late bone toxicity of grade 3 or 4 (1.0% vs. 0%; P < .05), as well as more late soft tissue (subcutaneous) toxicity overall (P < .001) and late soft tissue toxicity of grade 3 or 4 (2.6% vs. 1.1%; P < .05).
The two groups had essentially the same late lung toxicity.
Women treated with APBI had higher 5-year cumulative incidences of soft tissue toxicity of grade 2 or worse (29.7% vs. 17.9%; P < .0001) and grade 3 or worse (2.6% vs. 1.1%; P = .0016). Cumulative incidences of skin toxicity of these grades did not differ significantly.
Importantly, the prevalences of late soft tissue and skin toxicity at 5 years were much lower than the cumulative incidences, Dr. Meduri noted. “This means that the side effects in some patients tend to resolve over time.”
Although the prevalence of grade 2-4 skin toxicity increased slightly at 3 years and 5 years in both groups, the prevalence of grade 2-4 soft tissue toxicity was stable.
Finally, the volume that received at least 38.5 Gy of radiation was higher for patients who developed late grade 3 or 4 bone toxicity than for those who did not (2.1 vs. 0.82 cc; P = .027), whereas other dosimetric parameters were similar.
“The toxicity of the whole cohort was very low,” Dr. Meduri summarized. “APBI was associated with a slightly higher rate of late soft tissue and bone toxicity, with a slight decrease in cosmetic outcome at 5 years. But longer follow-up is needed to confirm these results.”
The IRMA findings confirm previous results from the RAPID trial showing that APBI delivered via 3D-conformal radiotherapy may be associated with increased rates of toxicity, Chirag Shah, MD, a radiation oncologist at the Cleveland Clinic in Ohio, said in an interview.
“While cancer control outcomes were not presented, the toxicity outcomes are important and validate why many are moving away from 3D-conformal radiotherapy APBI,” he elaborated. “We are seeing increased use of APBI in some centers in the U.S., though there has been a greater shift to IMRT [intensity-modulated radiation therapy] based on 10-year data from the Florence randomized trial, which showed reduced side effects.”
“I think the results of this study are practice-confirming,” Dr. Shah concluded. “Moving forward, shorter APBI schedules will be considered as we now have 5-fraction whole-breast regimens available, as assessed in the FAST and FAST-Forward trials.”
Dr. Meduri disclosed expert board service for MSD, and financial support for attending congresses from Ipsen, AstraZeneca, and Merck. The trial was sponsored by Regione Emilia-Romagna. Dr. Shah disclosed consulting for Impedimed and PreludeDX, and receiving grants from Varian, VisionRT, and PreludeDX.
SOURCE: Meduri B et al. ESTRO 2020. Abstract OC-0611.
Long-term cosmetic and toxicity outcomes are good for both accelerated partial breast irradiation (APBI) delivered with 3D-conformal radiotherapy and whole-breast irradiation (WBI), with the latter having a slight edge, the IRMA trial shows.
Findings were reported at the European Society for Radiology and Oncology 2020 Online Congress by Bruno Meduri, MD, a radiation oncologist at University Hospital of Modena, Italy.
Uptake of APBI has increased since it was approved nearly 2 decades ago. However, its long-term outcomes are still being parsed, and issues such as appropriate patient selection and optimal delivery technique are still being clarified (Curr Breast Cancer Rep. 2020;18:1-10).
IRMA is a European, multicenter, phase 3 randomized controlled trial conducted among 3,279 women aged 49 years and older who underwent breast-conserving surgery for early-stage breast cancer (measuring <3 cm in diameter, and pathologic N0 or N1) with negative resection margins.
The women were randomized to APBI using 3D-conformal radiotherapy (38.5 Gy in 10 fractions, twice daily) or conventional or hypofractionated WBI (50.0 Gy in 25 fractions, once daily). All additionally received adjuvant therapy according to institutional guidelines.
Patients and physicians separately rated cosmetic outcomes on a 4-point scale using the untreated breast as a reference, and toxicity was graded with the Radiation Therapy Oncology Group (RTOG) scale.
Over a median follow-up of 5 years, patients rated cosmesis more favorably than physicians did at all time points, and there was a trend toward slight worsening of cosmesis in the APBI group with time, Dr. Meduri reported.
At 1 year, cosmesis did not differ significantly between treatment groups regardless of the rater. But compared with the WBI group, the APBI group more often had patient-rated fair to poor cosmesis at 3 years (12.7% vs. 9.4%; P =.02) and at 5 years (15.0% vs. 10.1%; P = .007), as well as physician-rated fair to poor cosmesis at 3 years (18.0% vs. 13.1%; P = .003) and at 5 years (18.4% vs. 14.2%; P = .04).
Women treated with APBI had less acute skin toxicity (P < .001), with 4.9% developing grade 2 toxicity, compared with 21.4% of peers treated with WBI. Late skin toxicity was also less common in the APBI group overall (P < .001), but the rate of grade 3 or 4 late skin toxicity was similar.
On the other hand, the APBI group had more late bone toxicity overall (P < .001) and late bone toxicity of grade 3 or 4 (1.0% vs. 0%; P < .05), as well as more late soft tissue (subcutaneous) toxicity overall (P < .001) and late soft tissue toxicity of grade 3 or 4 (2.6% vs. 1.1%; P < .05).
The two groups had essentially the same late lung toxicity.
Women treated with APBI had higher 5-year cumulative incidences of soft tissue toxicity of grade 2 or worse (29.7% vs. 17.9%; P < .0001) and grade 3 or worse (2.6% vs. 1.1%; P = .0016). Cumulative incidences of skin toxicity of these grades did not differ significantly.
Importantly, the prevalences of late soft tissue and skin toxicity at 5 years were much lower than the cumulative incidences, Dr. Meduri noted. “This means that the side effects in some patients tend to resolve over time.”
Although the prevalence of grade 2-4 skin toxicity increased slightly at 3 years and 5 years in both groups, the prevalence of grade 2-4 soft tissue toxicity was stable.
Finally, the volume that received at least 38.5 Gy of radiation was higher for patients who developed late grade 3 or 4 bone toxicity than for those who did not (2.1 vs. 0.82 cc; P = .027), whereas other dosimetric parameters were similar.
“The toxicity of the whole cohort was very low,” Dr. Meduri summarized. “APBI was associated with a slightly higher rate of late soft tissue and bone toxicity, with a slight decrease in cosmetic outcome at 5 years. But longer follow-up is needed to confirm these results.”
The IRMA findings confirm previous results from the RAPID trial showing that APBI delivered via 3D-conformal radiotherapy may be associated with increased rates of toxicity, Chirag Shah, MD, a radiation oncologist at the Cleveland Clinic in Ohio, said in an interview.
“While cancer control outcomes were not presented, the toxicity outcomes are important and validate why many are moving away from 3D-conformal radiotherapy APBI,” he elaborated. “We are seeing increased use of APBI in some centers in the U.S., though there has been a greater shift to IMRT [intensity-modulated radiation therapy] based on 10-year data from the Florence randomized trial, which showed reduced side effects.”
“I think the results of this study are practice-confirming,” Dr. Shah concluded. “Moving forward, shorter APBI schedules will be considered as we now have 5-fraction whole-breast regimens available, as assessed in the FAST and FAST-Forward trials.”
Dr. Meduri disclosed expert board service for MSD, and financial support for attending congresses from Ipsen, AstraZeneca, and Merck. The trial was sponsored by Regione Emilia-Romagna. Dr. Shah disclosed consulting for Impedimed and PreludeDX, and receiving grants from Varian, VisionRT, and PreludeDX.
SOURCE: Meduri B et al. ESTRO 2020. Abstract OC-0611.
FROM ESTRO 2020
Omitting postop radiotherapy doesn’t affect survival in older breast cancer patients
Skipping whole-breast adjuvant radiotherapy does not appear to affect long-term survival in women age 65 and older who have had surgery for early-stage, hormone receptor–positive (HR+) breast cancer, according to 10-year follow-up of the phase 3 PRIME-2 study.
Although the risk for local recurrence was higher among patients who did not receive radiotherapy, the absolute risk for recurrence was still low, said study investigator Ian Kunkler, MRCPUK, FRCR, of Western General Hospital, University of Edinburgh in Scotland.
Dr. Kunkler presented results from PRIME-2 at the 2020 San Antonio Breast Cancer Symposium.
“In older patients, we have to carefully balance benefits [of radiotherapy] in terms of local control and survival against toxicities,” Dr. Kunkler said in an interview.
Omitting radiotherapy could help women avoid complications such as fatigue, changes to lung function, and an increased risk of cardiovascular damage.
“We think that these results should provide some reassurance that the omission of radiotherapy could be an option,” Dr. Kunkler said.
PRIME-2 results
The PRIME-2 study was a randomized trial that recruited 1,326 women with histologically confirmed, unilateral invasive breast cancer who were all 65 years or older.
For inclusion, the women had to have a tumor measuring 3 cm or less, have no nodal involvement, and be about to undergo breast-conserving surgery. Women also needed to be HR+ and be treated with adjuvant endocrine therapy.
The women were randomized 1:1 to receive adjuvant whole-breast irradiation at a dosing schedule of 40-50 Gy in 15-25 fractions or no radiotherapy in addition to adjuvant endocrine therapy.
The primary endpoint was the recurrence of breast cancer in the same breast at 10 years. There was a significantly lower rate of ipsilateral recurrence with radiotherapy than without it, at 0.9% and 9.8%, respectively (P = .00008).
Similarly, the 10-year rate of regional recurrence was significantly lower in the radiotherapy arm than in the no-radiotherapy arm (0.5% vs. 2.3%, P = .014).
However, there was no significant difference in the radiotherapy and nonradiotherapy arms when it came to distant recurrence (3.6% vs. 1.9%, P = .07), contralateral recurrence (2.2% vs. 1.2%, P = .20), or new, non–breast cancer (8.7% vs. 10.2%, P = .41).
The overall survival estimate at 10 years was 80.4% in women who did not receive radiotherapy and 81.0% in those who did (P = .68). Rates of metastasis-free survival were also similar (98.1% vs. 96.4%, P = .28).
“Most of these women are dying from non–breast cancer causes, reflecting the impact of competitive causes of non–breast cancer mortality,” Dr. Kunkler said.
Implications for practice
The current findings build on prior findings from the PRIME-2 study 5 years ago, which showed a small benefit of postoperative radiotherapy over no radiotherapy in reducing the rate of local recurrence. This led to the recommendation that postoperative radiotherapy might be safely omitted in some older women and influenced U.K. practice.
Indeed, Dr. Kunkler observed that U.K. guidelines have pretty much adopted the entry criteria for the PRIME-2 study (HR+, axillary node-negative [N0], T1–T2 up to 3 cm at the longest dimension, and clear margins) for the omission of radiotherapy.
“It’s had much less impact in the United States, where the usage of radiotherapy after breast-conserving surgery still remains very high,” Dr. Kunkler said.
He acknowledged that the current U.S. guidelines include the omission of radiotherapy in older women, but only those with much smaller (T1, N0) tumors, based on the findings of the Cancer and Leukemia Group B (CALGB) 9343 study.
“The findings from PRIME-2 so far seem consistent with long-term findings from CALGB 9343,” Matthew Katz, MD, of Lowell (Mass.) General Hospital Cancer Center, said in an interview.
However, “the median follow-up of the study was only 7 years, so it’s a little early to analyze 10-year data,” he added.
As to why leaving out radiotherapy in older women may be less common in the United States than in the U.K., Dr. Katz said it was probably due to a “tendency on the part of U.S. oncologists and cancer patients to lean more toward treatment to lower the risk of recurrence.
“When I discuss omitting radiation to women 70 or older with an early-stage, low risk breast cancer, the majority of people I see choose treatment,” he said. “The key is that a cancer patient can make informed choices about treatment based upon her or his values, looking at both the risks of cancer recurrence and the side effects of cancer treatments.”
“The decision as to whether radiotherapy is omitted or not has become a bit more nuanced,” since the PRIME-2 study started in 2003, Dr. Kunkler acknowledged.
He said there’s now evidence to suggest that shorter radiotherapy regimens may be beneficial. For example, the FAST-Forward trial showed that a regimen of 26 Gy in five fractions over 1 week was noninferior to a regimen of 40 Gy in 15 fractions over 3 weeks.
“There are really only two studies – the PRIME-2 study and the CALGB 9343 study – which are specific to an older age group,” Dr. Kunkler noted. “Most of the previous studies of breast-conserving surgery with or without radiotherapy receiving endocrine therapy have been predominantly in women under the age of 70. And indeed, 70 was often considered an exclusion criterion for randomized trials.”
PRIME-2 was funded by the Chief Scientist Office (Scottish Government) and the Breast Cancer Institute at the Western General Hospital in Edinburgh, Scotland. Neither Dr. Kunkler nor Dr. Katz had relevant disclosures.
SOURCE: Kunkler IH J et al. SABCS 2020, Abstract GS2-03.
Skipping whole-breast adjuvant radiotherapy does not appear to affect long-term survival in women age 65 and older who have had surgery for early-stage, hormone receptor–positive (HR+) breast cancer, according to 10-year follow-up of the phase 3 PRIME-2 study.
Although the risk for local recurrence was higher among patients who did not receive radiotherapy, the absolute risk for recurrence was still low, said study investigator Ian Kunkler, MRCPUK, FRCR, of Western General Hospital, University of Edinburgh in Scotland.
Dr. Kunkler presented results from PRIME-2 at the 2020 San Antonio Breast Cancer Symposium.
“In older patients, we have to carefully balance benefits [of radiotherapy] in terms of local control and survival against toxicities,” Dr. Kunkler said in an interview.
Omitting radiotherapy could help women avoid complications such as fatigue, changes to lung function, and an increased risk of cardiovascular damage.
“We think that these results should provide some reassurance that the omission of radiotherapy could be an option,” Dr. Kunkler said.
PRIME-2 results
The PRIME-2 study was a randomized trial that recruited 1,326 women with histologically confirmed, unilateral invasive breast cancer who were all 65 years or older.
For inclusion, the women had to have a tumor measuring 3 cm or less, have no nodal involvement, and be about to undergo breast-conserving surgery. Women also needed to be HR+ and be treated with adjuvant endocrine therapy.
The women were randomized 1:1 to receive adjuvant whole-breast irradiation at a dosing schedule of 40-50 Gy in 15-25 fractions or no radiotherapy in addition to adjuvant endocrine therapy.
The primary endpoint was the recurrence of breast cancer in the same breast at 10 years. There was a significantly lower rate of ipsilateral recurrence with radiotherapy than without it, at 0.9% and 9.8%, respectively (P = .00008).
Similarly, the 10-year rate of regional recurrence was significantly lower in the radiotherapy arm than in the no-radiotherapy arm (0.5% vs. 2.3%, P = .014).
However, there was no significant difference in the radiotherapy and nonradiotherapy arms when it came to distant recurrence (3.6% vs. 1.9%, P = .07), contralateral recurrence (2.2% vs. 1.2%, P = .20), or new, non–breast cancer (8.7% vs. 10.2%, P = .41).
The overall survival estimate at 10 years was 80.4% in women who did not receive radiotherapy and 81.0% in those who did (P = .68). Rates of metastasis-free survival were also similar (98.1% vs. 96.4%, P = .28).
“Most of these women are dying from non–breast cancer causes, reflecting the impact of competitive causes of non–breast cancer mortality,” Dr. Kunkler said.
Implications for practice
The current findings build on prior findings from the PRIME-2 study 5 years ago, which showed a small benefit of postoperative radiotherapy over no radiotherapy in reducing the rate of local recurrence. This led to the recommendation that postoperative radiotherapy might be safely omitted in some older women and influenced U.K. practice.
Indeed, Dr. Kunkler observed that U.K. guidelines have pretty much adopted the entry criteria for the PRIME-2 study (HR+, axillary node-negative [N0], T1–T2 up to 3 cm at the longest dimension, and clear margins) for the omission of radiotherapy.
“It’s had much less impact in the United States, where the usage of radiotherapy after breast-conserving surgery still remains very high,” Dr. Kunkler said.
He acknowledged that the current U.S. guidelines include the omission of radiotherapy in older women, but only those with much smaller (T1, N0) tumors, based on the findings of the Cancer and Leukemia Group B (CALGB) 9343 study.
“The findings from PRIME-2 so far seem consistent with long-term findings from CALGB 9343,” Matthew Katz, MD, of Lowell (Mass.) General Hospital Cancer Center, said in an interview.
However, “the median follow-up of the study was only 7 years, so it’s a little early to analyze 10-year data,” he added.
As to why leaving out radiotherapy in older women may be less common in the United States than in the U.K., Dr. Katz said it was probably due to a “tendency on the part of U.S. oncologists and cancer patients to lean more toward treatment to lower the risk of recurrence.
“When I discuss omitting radiation to women 70 or older with an early-stage, low risk breast cancer, the majority of people I see choose treatment,” he said. “The key is that a cancer patient can make informed choices about treatment based upon her or his values, looking at both the risks of cancer recurrence and the side effects of cancer treatments.”
“The decision as to whether radiotherapy is omitted or not has become a bit more nuanced,” since the PRIME-2 study started in 2003, Dr. Kunkler acknowledged.
He said there’s now evidence to suggest that shorter radiotherapy regimens may be beneficial. For example, the FAST-Forward trial showed that a regimen of 26 Gy in five fractions over 1 week was noninferior to a regimen of 40 Gy in 15 fractions over 3 weeks.
“There are really only two studies – the PRIME-2 study and the CALGB 9343 study – which are specific to an older age group,” Dr. Kunkler noted. “Most of the previous studies of breast-conserving surgery with or without radiotherapy receiving endocrine therapy have been predominantly in women under the age of 70. And indeed, 70 was often considered an exclusion criterion for randomized trials.”
PRIME-2 was funded by the Chief Scientist Office (Scottish Government) and the Breast Cancer Institute at the Western General Hospital in Edinburgh, Scotland. Neither Dr. Kunkler nor Dr. Katz had relevant disclosures.
SOURCE: Kunkler IH J et al. SABCS 2020, Abstract GS2-03.
Skipping whole-breast adjuvant radiotherapy does not appear to affect long-term survival in women age 65 and older who have had surgery for early-stage, hormone receptor–positive (HR+) breast cancer, according to 10-year follow-up of the phase 3 PRIME-2 study.
Although the risk for local recurrence was higher among patients who did not receive radiotherapy, the absolute risk for recurrence was still low, said study investigator Ian Kunkler, MRCPUK, FRCR, of Western General Hospital, University of Edinburgh in Scotland.
Dr. Kunkler presented results from PRIME-2 at the 2020 San Antonio Breast Cancer Symposium.
“In older patients, we have to carefully balance benefits [of radiotherapy] in terms of local control and survival against toxicities,” Dr. Kunkler said in an interview.
Omitting radiotherapy could help women avoid complications such as fatigue, changes to lung function, and an increased risk of cardiovascular damage.
“We think that these results should provide some reassurance that the omission of radiotherapy could be an option,” Dr. Kunkler said.
PRIME-2 results
The PRIME-2 study was a randomized trial that recruited 1,326 women with histologically confirmed, unilateral invasive breast cancer who were all 65 years or older.
For inclusion, the women had to have a tumor measuring 3 cm or less, have no nodal involvement, and be about to undergo breast-conserving surgery. Women also needed to be HR+ and be treated with adjuvant endocrine therapy.
The women were randomized 1:1 to receive adjuvant whole-breast irradiation at a dosing schedule of 40-50 Gy in 15-25 fractions or no radiotherapy in addition to adjuvant endocrine therapy.
The primary endpoint was the recurrence of breast cancer in the same breast at 10 years. There was a significantly lower rate of ipsilateral recurrence with radiotherapy than without it, at 0.9% and 9.8%, respectively (P = .00008).
Similarly, the 10-year rate of regional recurrence was significantly lower in the radiotherapy arm than in the no-radiotherapy arm (0.5% vs. 2.3%, P = .014).
However, there was no significant difference in the radiotherapy and nonradiotherapy arms when it came to distant recurrence (3.6% vs. 1.9%, P = .07), contralateral recurrence (2.2% vs. 1.2%, P = .20), or new, non–breast cancer (8.7% vs. 10.2%, P = .41).
The overall survival estimate at 10 years was 80.4% in women who did not receive radiotherapy and 81.0% in those who did (P = .68). Rates of metastasis-free survival were also similar (98.1% vs. 96.4%, P = .28).
“Most of these women are dying from non–breast cancer causes, reflecting the impact of competitive causes of non–breast cancer mortality,” Dr. Kunkler said.
Implications for practice
The current findings build on prior findings from the PRIME-2 study 5 years ago, which showed a small benefit of postoperative radiotherapy over no radiotherapy in reducing the rate of local recurrence. This led to the recommendation that postoperative radiotherapy might be safely omitted in some older women and influenced U.K. practice.
Indeed, Dr. Kunkler observed that U.K. guidelines have pretty much adopted the entry criteria for the PRIME-2 study (HR+, axillary node-negative [N0], T1–T2 up to 3 cm at the longest dimension, and clear margins) for the omission of radiotherapy.
“It’s had much less impact in the United States, where the usage of radiotherapy after breast-conserving surgery still remains very high,” Dr. Kunkler said.
He acknowledged that the current U.S. guidelines include the omission of radiotherapy in older women, but only those with much smaller (T1, N0) tumors, based on the findings of the Cancer and Leukemia Group B (CALGB) 9343 study.
“The findings from PRIME-2 so far seem consistent with long-term findings from CALGB 9343,” Matthew Katz, MD, of Lowell (Mass.) General Hospital Cancer Center, said in an interview.
However, “the median follow-up of the study was only 7 years, so it’s a little early to analyze 10-year data,” he added.
As to why leaving out radiotherapy in older women may be less common in the United States than in the U.K., Dr. Katz said it was probably due to a “tendency on the part of U.S. oncologists and cancer patients to lean more toward treatment to lower the risk of recurrence.
“When I discuss omitting radiation to women 70 or older with an early-stage, low risk breast cancer, the majority of people I see choose treatment,” he said. “The key is that a cancer patient can make informed choices about treatment based upon her or his values, looking at both the risks of cancer recurrence and the side effects of cancer treatments.”
“The decision as to whether radiotherapy is omitted or not has become a bit more nuanced,” since the PRIME-2 study started in 2003, Dr. Kunkler acknowledged.
He said there’s now evidence to suggest that shorter radiotherapy regimens may be beneficial. For example, the FAST-Forward trial showed that a regimen of 26 Gy in five fractions over 1 week was noninferior to a regimen of 40 Gy in 15 fractions over 3 weeks.
“There are really only two studies – the PRIME-2 study and the CALGB 9343 study – which are specific to an older age group,” Dr. Kunkler noted. “Most of the previous studies of breast-conserving surgery with or without radiotherapy receiving endocrine therapy have been predominantly in women under the age of 70. And indeed, 70 was often considered an exclusion criterion for randomized trials.”
PRIME-2 was funded by the Chief Scientist Office (Scottish Government) and the Breast Cancer Institute at the Western General Hospital in Edinburgh, Scotland. Neither Dr. Kunkler nor Dr. Katz had relevant disclosures.
SOURCE: Kunkler IH J et al. SABCS 2020, Abstract GS2-03.
FROM SABCS 2020
Margetuximab approved for HER2-positive metastatic breast cancer
The new drug is indicated for use in combination with chemotherapy for the treatment of patients with metastatic HER2-positive breast cancer who have already received two or more prior anti-HER2 regimens, with at least one for metastatic disease.
Margetuximab-cmkb is also the first HER2-targeted therapy shown to improve progression-free survival (PFS) as compared with the first-ever HER2-targeted agent, trastuzumab in a head-to-head, phase 3 clinical trial (known as SOPHIA).
“Early detection and treatment have had a positive impact on the survival of patients with breast cancer, but the prognosis for people diagnosed with metastatic breast cancer remains poor, and additional treatments are needed,” said Hope S. Rugo, MD, director of breast oncology and clinical trials education, University of California, San Francisco, Diller Family Comprehensive Cancer Center, in a press release.
“As the only HER2-targeted agent to have shown a PFS improvement versus trastuzumab in a head-to-head phase 3 clinical trial, margetuximab with chemotherapy represents the newest treatment option for patients who have progressed on available HER2-directed therapies,” said Dr. Rugo, who is an investigator in the SOPHIA trial.
Like trastuzumab, margetuximab-cmkb binds HER2 with high specificity and affinity and disrupts signaling that drives cell proliferation and survival, but margetuximab binds with elevated affinity to both the lower- and higher-affinity forms of CD16A, an Fc gamma receptor important for antibody dependent cell-mediated cytotoxicity against tumor cells, according to the manufacturer, MacroGenics.
Details of the pivotal trial
The SOPHIA trial was a randomized, open-label, phase 3 clinical trial that compared margetuximab-cmkb plus chemotherapy with trastuzumab plus chemotherapy in both arms in patients with HER2-positive metastatic breast cancer who had previously been treated with anti–HER2-targeted therapies.
All patients in the cohort had previously received trastuzumab, all but one patient had previously also received pertuzumab, and most of the patients (91%) had also been treated with ado-trastuzumab emtansine, or T-DM1.
The trial randomly assigned 536 patients to receive either margetuximab-cmkb (n = 266) given intravenously at 15 mg/kg every 3 weeks or trastuzumab (n = 270) given intravenously at 6 mg/kg (or 8 mg/kg for loading dose) every 3 weeks in combination with either capecitabine, eribulin, gemcitabine, or vinorelbine, given at the standard doses.
As compared with trastuzumab, margetuximab plus chemotherapy led to a significant 24% reduction in the risk for progression or death (hazard ratio, 0.76).
The median PFS also favored margetuximab (5.8 months vs. 4.9 months), as did the overall response rate (22% vs. 16%).
The final overall survival analysis is expected in the second half of 2021.
Common adverse events associated with the margetuximab regimen included fatigue/asthenia (57%), nausea (33%), diarrhea (25%), and vomiting (21%). Infusion-related reactions occurred in 13% of patients receiving margetuximab, and almost all were grade 1 or 2, with only 1.5% at grade 3.
The product also carries a boxed warning for left ventricular dysfunction and embryo-fetal toxicity.
A version of this article first appeared on Medscape.com.
The new drug is indicated for use in combination with chemotherapy for the treatment of patients with metastatic HER2-positive breast cancer who have already received two or more prior anti-HER2 regimens, with at least one for metastatic disease.
Margetuximab-cmkb is also the first HER2-targeted therapy shown to improve progression-free survival (PFS) as compared with the first-ever HER2-targeted agent, trastuzumab in a head-to-head, phase 3 clinical trial (known as SOPHIA).
“Early detection and treatment have had a positive impact on the survival of patients with breast cancer, but the prognosis for people diagnosed with metastatic breast cancer remains poor, and additional treatments are needed,” said Hope S. Rugo, MD, director of breast oncology and clinical trials education, University of California, San Francisco, Diller Family Comprehensive Cancer Center, in a press release.
“As the only HER2-targeted agent to have shown a PFS improvement versus trastuzumab in a head-to-head phase 3 clinical trial, margetuximab with chemotherapy represents the newest treatment option for patients who have progressed on available HER2-directed therapies,” said Dr. Rugo, who is an investigator in the SOPHIA trial.
Like trastuzumab, margetuximab-cmkb binds HER2 with high specificity and affinity and disrupts signaling that drives cell proliferation and survival, but margetuximab binds with elevated affinity to both the lower- and higher-affinity forms of CD16A, an Fc gamma receptor important for antibody dependent cell-mediated cytotoxicity against tumor cells, according to the manufacturer, MacroGenics.
Details of the pivotal trial
The SOPHIA trial was a randomized, open-label, phase 3 clinical trial that compared margetuximab-cmkb plus chemotherapy with trastuzumab plus chemotherapy in both arms in patients with HER2-positive metastatic breast cancer who had previously been treated with anti–HER2-targeted therapies.
All patients in the cohort had previously received trastuzumab, all but one patient had previously also received pertuzumab, and most of the patients (91%) had also been treated with ado-trastuzumab emtansine, or T-DM1.
The trial randomly assigned 536 patients to receive either margetuximab-cmkb (n = 266) given intravenously at 15 mg/kg every 3 weeks or trastuzumab (n = 270) given intravenously at 6 mg/kg (or 8 mg/kg for loading dose) every 3 weeks in combination with either capecitabine, eribulin, gemcitabine, or vinorelbine, given at the standard doses.
As compared with trastuzumab, margetuximab plus chemotherapy led to a significant 24% reduction in the risk for progression or death (hazard ratio, 0.76).
The median PFS also favored margetuximab (5.8 months vs. 4.9 months), as did the overall response rate (22% vs. 16%).
The final overall survival analysis is expected in the second half of 2021.
Common adverse events associated with the margetuximab regimen included fatigue/asthenia (57%), nausea (33%), diarrhea (25%), and vomiting (21%). Infusion-related reactions occurred in 13% of patients receiving margetuximab, and almost all were grade 1 or 2, with only 1.5% at grade 3.
The product also carries a boxed warning for left ventricular dysfunction and embryo-fetal toxicity.
A version of this article first appeared on Medscape.com.
The new drug is indicated for use in combination with chemotherapy for the treatment of patients with metastatic HER2-positive breast cancer who have already received two or more prior anti-HER2 regimens, with at least one for metastatic disease.
Margetuximab-cmkb is also the first HER2-targeted therapy shown to improve progression-free survival (PFS) as compared with the first-ever HER2-targeted agent, trastuzumab in a head-to-head, phase 3 clinical trial (known as SOPHIA).
“Early detection and treatment have had a positive impact on the survival of patients with breast cancer, but the prognosis for people diagnosed with metastatic breast cancer remains poor, and additional treatments are needed,” said Hope S. Rugo, MD, director of breast oncology and clinical trials education, University of California, San Francisco, Diller Family Comprehensive Cancer Center, in a press release.
“As the only HER2-targeted agent to have shown a PFS improvement versus trastuzumab in a head-to-head phase 3 clinical trial, margetuximab with chemotherapy represents the newest treatment option for patients who have progressed on available HER2-directed therapies,” said Dr. Rugo, who is an investigator in the SOPHIA trial.
Like trastuzumab, margetuximab-cmkb binds HER2 with high specificity and affinity and disrupts signaling that drives cell proliferation and survival, but margetuximab binds with elevated affinity to both the lower- and higher-affinity forms of CD16A, an Fc gamma receptor important for antibody dependent cell-mediated cytotoxicity against tumor cells, according to the manufacturer, MacroGenics.
Details of the pivotal trial
The SOPHIA trial was a randomized, open-label, phase 3 clinical trial that compared margetuximab-cmkb plus chemotherapy with trastuzumab plus chemotherapy in both arms in patients with HER2-positive metastatic breast cancer who had previously been treated with anti–HER2-targeted therapies.
All patients in the cohort had previously received trastuzumab, all but one patient had previously also received pertuzumab, and most of the patients (91%) had also been treated with ado-trastuzumab emtansine, or T-DM1.
The trial randomly assigned 536 patients to receive either margetuximab-cmkb (n = 266) given intravenously at 15 mg/kg every 3 weeks or trastuzumab (n = 270) given intravenously at 6 mg/kg (or 8 mg/kg for loading dose) every 3 weeks in combination with either capecitabine, eribulin, gemcitabine, or vinorelbine, given at the standard doses.
As compared with trastuzumab, margetuximab plus chemotherapy led to a significant 24% reduction in the risk for progression or death (hazard ratio, 0.76).
The median PFS also favored margetuximab (5.8 months vs. 4.9 months), as did the overall response rate (22% vs. 16%).
The final overall survival analysis is expected in the second half of 2021.
Common adverse events associated with the margetuximab regimen included fatigue/asthenia (57%), nausea (33%), diarrhea (25%), and vomiting (21%). Infusion-related reactions occurred in 13% of patients receiving margetuximab, and almost all were grade 1 or 2, with only 1.5% at grade 3.
The product also carries a boxed warning for left ventricular dysfunction and embryo-fetal toxicity.
A version of this article first appeared on Medscape.com.
Most common cancer diagnosis globally: Breast surpasses lung
Breast cancer now tops the list of the most commonly diagnosed cancers worldwide, surpassing lung cancer for the first time, according to the latest global cancer burden estimates from the International Agency for Research on Cancer (IARC).
Breast cancer among women accounted for 11.7% of the estimated 19.3 million new cancer cases in 2020 ― and about 25% of all cancer cases among women. Lung cancer accounted for 11.4% of new cases, reports the IARC, part of the World Health Organization.
However, lung cancer remains the leading overall cause of cancer mortality, accounting for 18.0% of 10 million cancer deaths. Breast cancer ranks fifth as a cause of cancer mortality, accounting for 1 of every 6 cancer deaths in women and 685,000 deaths overall (6.9%) in 2020, but it ranks first in incidence in 159 countries and first in mortality in 110 countries, the data show.
The increase in breast cancer cases is likely attributable to the effects of “marked changes in lifestyle, sociocultural contexts, and built environments” in many countries, says the IACR. These include delayed childbearing, having fewer children, increased rates of overweight and obesity, and decreasing levels of physical activity, the IACR explains in a press release.
These new data underscore the importance of focusing on cancer prevention, IARC Director Elisabete Weiderpass, MD, states in the press release.
“Effective interventions for prevention and early detection are available and must be integrated into cancer planning to control the predicted upsurge of this devastating disease,” she said.
Weiderpass also notes that the “overwhelming need for evidence-based and resource-stratified guidelines that support the phased implementation of breast cancer early detection and treatment into real-world practice.”
To that end, the WHO and the IARC will launch a global breast cancer initiative in 2021 to improve population-level outcomes through a focus on more timely diagnosis and comprehensive treatment, she adds.
The most common cancer diagnoses worldwide after breast cancer and lung cancer are colorectal cancer (10.0%), prostate cancer (7.3%), and stomach cancer (5.6%).
The leading causes of cancer deaths after lung cancer are colorectal cancer (9.4%), liver cancer (8.3%), stomach cancer (7.7%), and breast cancer among women.
One in five people will develop cancer
The IACR estimates that 1 in 5 people will develop cancer in their lifetime and that 1 in 8 men and 1 in 11 women will die from it.
Among women, breast cancer is the most common cancer type and the most common cause of cancer death. Colorectal cancer and lung cancer are the second and third most common cancer types and the third and second most common causes of cancer death, respectively.
Among men, lung cancer is the most common cancer type and the most common cause of cancer death. Prostate cancer and colorectal cancer are the second and third most common cancer types, and liver cancer and colorectal cancer are the second and third most common causes of cancer death.
“Worldwide, an estimated 28.4 million new cancer cases are projected to occur in 2040, a 47% increase from the estimated 19.3 million cases in 2020,” the IARC notes.
The agency derives its estimates from the GLOBOCAN 2020 database, which tracks 185 countries and 36 types of cancer and is accessible through the IARC Global Cancer Observatory.
A version of this article first appeared on Medscape.com.
Breast cancer now tops the list of the most commonly diagnosed cancers worldwide, surpassing lung cancer for the first time, according to the latest global cancer burden estimates from the International Agency for Research on Cancer (IARC).
Breast cancer among women accounted for 11.7% of the estimated 19.3 million new cancer cases in 2020 ― and about 25% of all cancer cases among women. Lung cancer accounted for 11.4% of new cases, reports the IARC, part of the World Health Organization.
However, lung cancer remains the leading overall cause of cancer mortality, accounting for 18.0% of 10 million cancer deaths. Breast cancer ranks fifth as a cause of cancer mortality, accounting for 1 of every 6 cancer deaths in women and 685,000 deaths overall (6.9%) in 2020, but it ranks first in incidence in 159 countries and first in mortality in 110 countries, the data show.
The increase in breast cancer cases is likely attributable to the effects of “marked changes in lifestyle, sociocultural contexts, and built environments” in many countries, says the IACR. These include delayed childbearing, having fewer children, increased rates of overweight and obesity, and decreasing levels of physical activity, the IACR explains in a press release.
These new data underscore the importance of focusing on cancer prevention, IARC Director Elisabete Weiderpass, MD, states in the press release.
“Effective interventions for prevention and early detection are available and must be integrated into cancer planning to control the predicted upsurge of this devastating disease,” she said.
Weiderpass also notes that the “overwhelming need for evidence-based and resource-stratified guidelines that support the phased implementation of breast cancer early detection and treatment into real-world practice.”
To that end, the WHO and the IARC will launch a global breast cancer initiative in 2021 to improve population-level outcomes through a focus on more timely diagnosis and comprehensive treatment, she adds.
The most common cancer diagnoses worldwide after breast cancer and lung cancer are colorectal cancer (10.0%), prostate cancer (7.3%), and stomach cancer (5.6%).
The leading causes of cancer deaths after lung cancer are colorectal cancer (9.4%), liver cancer (8.3%), stomach cancer (7.7%), and breast cancer among women.
One in five people will develop cancer
The IACR estimates that 1 in 5 people will develop cancer in their lifetime and that 1 in 8 men and 1 in 11 women will die from it.
Among women, breast cancer is the most common cancer type and the most common cause of cancer death. Colorectal cancer and lung cancer are the second and third most common cancer types and the third and second most common causes of cancer death, respectively.
Among men, lung cancer is the most common cancer type and the most common cause of cancer death. Prostate cancer and colorectal cancer are the second and third most common cancer types, and liver cancer and colorectal cancer are the second and third most common causes of cancer death.
“Worldwide, an estimated 28.4 million new cancer cases are projected to occur in 2040, a 47% increase from the estimated 19.3 million cases in 2020,” the IARC notes.
The agency derives its estimates from the GLOBOCAN 2020 database, which tracks 185 countries and 36 types of cancer and is accessible through the IARC Global Cancer Observatory.
A version of this article first appeared on Medscape.com.
Breast cancer now tops the list of the most commonly diagnosed cancers worldwide, surpassing lung cancer for the first time, according to the latest global cancer burden estimates from the International Agency for Research on Cancer (IARC).
Breast cancer among women accounted for 11.7% of the estimated 19.3 million new cancer cases in 2020 ― and about 25% of all cancer cases among women. Lung cancer accounted for 11.4% of new cases, reports the IARC, part of the World Health Organization.
However, lung cancer remains the leading overall cause of cancer mortality, accounting for 18.0% of 10 million cancer deaths. Breast cancer ranks fifth as a cause of cancer mortality, accounting for 1 of every 6 cancer deaths in women and 685,000 deaths overall (6.9%) in 2020, but it ranks first in incidence in 159 countries and first in mortality in 110 countries, the data show.
The increase in breast cancer cases is likely attributable to the effects of “marked changes in lifestyle, sociocultural contexts, and built environments” in many countries, says the IACR. These include delayed childbearing, having fewer children, increased rates of overweight and obesity, and decreasing levels of physical activity, the IACR explains in a press release.
These new data underscore the importance of focusing on cancer prevention, IARC Director Elisabete Weiderpass, MD, states in the press release.
“Effective interventions for prevention and early detection are available and must be integrated into cancer planning to control the predicted upsurge of this devastating disease,” she said.
Weiderpass also notes that the “overwhelming need for evidence-based and resource-stratified guidelines that support the phased implementation of breast cancer early detection and treatment into real-world practice.”
To that end, the WHO and the IARC will launch a global breast cancer initiative in 2021 to improve population-level outcomes through a focus on more timely diagnosis and comprehensive treatment, she adds.
The most common cancer diagnoses worldwide after breast cancer and lung cancer are colorectal cancer (10.0%), prostate cancer (7.3%), and stomach cancer (5.6%).
The leading causes of cancer deaths after lung cancer are colorectal cancer (9.4%), liver cancer (8.3%), stomach cancer (7.7%), and breast cancer among women.
One in five people will develop cancer
The IACR estimates that 1 in 5 people will develop cancer in their lifetime and that 1 in 8 men and 1 in 11 women will die from it.
Among women, breast cancer is the most common cancer type and the most common cause of cancer death. Colorectal cancer and lung cancer are the second and third most common cancer types and the third and second most common causes of cancer death, respectively.
Among men, lung cancer is the most common cancer type and the most common cause of cancer death. Prostate cancer and colorectal cancer are the second and third most common cancer types, and liver cancer and colorectal cancer are the second and third most common causes of cancer death.
“Worldwide, an estimated 28.4 million new cancer cases are projected to occur in 2040, a 47% increase from the estimated 19.3 million cases in 2020,” the IARC notes.
The agency derives its estimates from the GLOBOCAN 2020 database, which tracks 185 countries and 36 types of cancer and is accessible through the IARC Global Cancer Observatory.
A version of this article first appeared on Medscape.com.
An all-oral option for advanced HR+, HER2– breast cancer?
These results suggest tesetaxel plus capecitabine is “a potential new treatment option” for this patient population, said study investigator Joyce O’Shaughnessy, MD, of Baylor University Medical Center and Texas Oncology, both in Dallas.
“This should launch an oral taxane into the clinical space, which will be a nice addition to the toolbox for treating advanced breast cancer, with real upsides for patients,” said Hal Burstein, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, who was not involved in the trial but commented on the results in an interview.
Another commenter was more critical of CONTESSA’s results, which were presented at the 2020 San Antonio Breast Cancer Symposium.
“Three months’ difference in PFS in this setting is meaningless without overall survival [OS] results,” Fatima Cardoso, MD, of Champalimaud Clinical Center in Lisbon, Portugal, said in a question submitted through the virtual meeting’s chat system.
At this point, the OS data are immature, and mature data won’t be available for another couple of years at least, according to the study’s protocol.
Dr. O’Shaughnessy defended the PFS result as being significant, however, saying it was comparable with outcomes seen previously with docetaxel-capecitabine and paclitaxel-gemcitabine combinations.
Other meeting attendees questioned why the waters had been muddied by testing the effects of tesetaxel in combination with capecitabine, albeit at a reduced dose, versus the approved full dose of capecitabine as monotherapy, particularly as a phase 2 trial had shown that tesetaxel demonstrated “significant activity” as monotherapy.
“The reason for the combination versus a monotherapy is because it was designed as a registration trial,” Dr. O’Shaughnessy explained. The trial was designed to be very similar to early taxane studies where docetaxel was assessed with or without capecitabine, or paclitaxel with or without gemcitabine.
“Probably we’re going to be using a doublet for patients who have virulent disease who really need a response,” Dr. O’Shaughnessy explained. She noted that the objective response rate was much higher with the tesetaxel-capecitabine combination than with capecitabine alone, and that result alone is “probably enough that we would utilize a doublet.”
The key thing is that it now gives patients an all-oral option, Dr. O’Shaughnessy said.
“The data are exciting because it would be terrific to have an orally available taxane chemotherapy,” agreed Dr. Burstein. “It is far more convenient for patients and opens access globally in places that do not have adequate resources for administration of IV therapeutics. Also, the data suggest that tesetaxel has a different side effect profile than IV taxane, with less neuropathy and less alopecia.”
Trial design
CONTESSA is an ongoing randomized, controlled trial that started in 2017 and is projected to end in early 2023. It is investigating the use of tesetaxel plus a reduced dose of capecitabine versus the approved dose of capecitabine alone in 685 women with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer who had previously been treated with a taxane.
Being intrinsically orally bioavailable and more soluble than the other taxanes means that tesetaxel has a much longer half-life that allows for a “more convenient treatment experience for patients,” Dr. O’Shaughnessy observed.
Indeed, because tesetaxel only needs to be dosed once every 3 weeks, patients in the trial received tesetaxel at 27 mg/m2 only on the first day of a 21-day treatment cycle. This was combined with a reduced, 825-mg/m2 dose of capecitabine, given orally twice-daily on days 2-14 but once daily on the evening of day 1 and on the morning of day 15.
The combination regimen was compared with the recommended full dose of capecitabine alone, 1,250 mg/m2 given orally twice daily on days 2-14 but once daily on the evening of day 1 and on the morning of day 15.
Efficacy and safety
PFS was 9.8 months with tesetaxel plus capecitabine and 6.9 months with capecitabine alone, representing a 2.9-month improvement with the combination (hazard ratio, 0.716; P = .003).
A similar PFS benefit was seen regardless of multiple predefined subgroups, such as age, baseline performance status, duration of disease-free interval before study entry, and the use of CDK4/6 inhibitors.
The objective response rate was 57% with tesetaxel plus capecitabine and 41% with capecitabine alone (P = .0002). The 24-week disease control rate was 67% and 50%, respectively (P < .0001).
The most frequent treatment-emergent adverse event seen with the tesetaxel-capecitabine combination was neutropenia, occurring in 76.9% of patients, compared with 22.6% of patients in the monotherapy arm. Rates of grade 3-4 neutropenia were much higher in the combination arm (32.6% and 38.3%, respectively) than in the monotherapy arm (7.4% and 0.9%, respectively).
The neutropenia seen was “generally manageable,” Dr. O’Shaughnessy said, primarily with dose reductions and granulocyte colony–stimulating factor as needed.
She pointed out that rates of grade 3 or higher neuropathy and grade 2 alopecia were low, a respective 5.9% and 8%, with the combination.
The dose of capecitabine used in the control arm was noted to be higher than that used in usual practice.
“This was because of the global nature of the study and the regulatory requirements globally,” Dr. O’Shaughnessy said.
“The dose-modification scheme was that patients could have a dose reduction at the first sign of grade 2 toxicity,” she added, giving investigators the flexibility to reduce the dose as soon as possible.
This study was sponsored by Odonate Therapeutics. Dr. O’Shaughnessy disclosed consulting fees from AbbVie, Agendia, AstraZeneca, Bristol-Myers Squibb, Celgene, Eisai, Genentech/Roche, Genomic Health, GRAIL, Heron, Immunomedics, Ipsen, Jounce, Lilly, Novartis, Odonate, Pfizer, Puma, and Seagen. Dr. Burstein and Dr. Cardoso had no relevant disclosures.
SOURCE: O’Shaughnessy J et al. SABCS 2020, Abstract GS4-01.
These results suggest tesetaxel plus capecitabine is “a potential new treatment option” for this patient population, said study investigator Joyce O’Shaughnessy, MD, of Baylor University Medical Center and Texas Oncology, both in Dallas.
“This should launch an oral taxane into the clinical space, which will be a nice addition to the toolbox for treating advanced breast cancer, with real upsides for patients,” said Hal Burstein, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, who was not involved in the trial but commented on the results in an interview.
Another commenter was more critical of CONTESSA’s results, which were presented at the 2020 San Antonio Breast Cancer Symposium.
“Three months’ difference in PFS in this setting is meaningless without overall survival [OS] results,” Fatima Cardoso, MD, of Champalimaud Clinical Center in Lisbon, Portugal, said in a question submitted through the virtual meeting’s chat system.
At this point, the OS data are immature, and mature data won’t be available for another couple of years at least, according to the study’s protocol.
Dr. O’Shaughnessy defended the PFS result as being significant, however, saying it was comparable with outcomes seen previously with docetaxel-capecitabine and paclitaxel-gemcitabine combinations.
Other meeting attendees questioned why the waters had been muddied by testing the effects of tesetaxel in combination with capecitabine, albeit at a reduced dose, versus the approved full dose of capecitabine as monotherapy, particularly as a phase 2 trial had shown that tesetaxel demonstrated “significant activity” as monotherapy.
“The reason for the combination versus a monotherapy is because it was designed as a registration trial,” Dr. O’Shaughnessy explained. The trial was designed to be very similar to early taxane studies where docetaxel was assessed with or without capecitabine, or paclitaxel with or without gemcitabine.
“Probably we’re going to be using a doublet for patients who have virulent disease who really need a response,” Dr. O’Shaughnessy explained. She noted that the objective response rate was much higher with the tesetaxel-capecitabine combination than with capecitabine alone, and that result alone is “probably enough that we would utilize a doublet.”
The key thing is that it now gives patients an all-oral option, Dr. O’Shaughnessy said.
“The data are exciting because it would be terrific to have an orally available taxane chemotherapy,” agreed Dr. Burstein. “It is far more convenient for patients and opens access globally in places that do not have adequate resources for administration of IV therapeutics. Also, the data suggest that tesetaxel has a different side effect profile than IV taxane, with less neuropathy and less alopecia.”
Trial design
CONTESSA is an ongoing randomized, controlled trial that started in 2017 and is projected to end in early 2023. It is investigating the use of tesetaxel plus a reduced dose of capecitabine versus the approved dose of capecitabine alone in 685 women with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer who had previously been treated with a taxane.
Being intrinsically orally bioavailable and more soluble than the other taxanes means that tesetaxel has a much longer half-life that allows for a “more convenient treatment experience for patients,” Dr. O’Shaughnessy observed.
Indeed, because tesetaxel only needs to be dosed once every 3 weeks, patients in the trial received tesetaxel at 27 mg/m2 only on the first day of a 21-day treatment cycle. This was combined with a reduced, 825-mg/m2 dose of capecitabine, given orally twice-daily on days 2-14 but once daily on the evening of day 1 and on the morning of day 15.
The combination regimen was compared with the recommended full dose of capecitabine alone, 1,250 mg/m2 given orally twice daily on days 2-14 but once daily on the evening of day 1 and on the morning of day 15.
Efficacy and safety
PFS was 9.8 months with tesetaxel plus capecitabine and 6.9 months with capecitabine alone, representing a 2.9-month improvement with the combination (hazard ratio, 0.716; P = .003).
A similar PFS benefit was seen regardless of multiple predefined subgroups, such as age, baseline performance status, duration of disease-free interval before study entry, and the use of CDK4/6 inhibitors.
The objective response rate was 57% with tesetaxel plus capecitabine and 41% with capecitabine alone (P = .0002). The 24-week disease control rate was 67% and 50%, respectively (P < .0001).
The most frequent treatment-emergent adverse event seen with the tesetaxel-capecitabine combination was neutropenia, occurring in 76.9% of patients, compared with 22.6% of patients in the monotherapy arm. Rates of grade 3-4 neutropenia were much higher in the combination arm (32.6% and 38.3%, respectively) than in the monotherapy arm (7.4% and 0.9%, respectively).
The neutropenia seen was “generally manageable,” Dr. O’Shaughnessy said, primarily with dose reductions and granulocyte colony–stimulating factor as needed.
She pointed out that rates of grade 3 or higher neuropathy and grade 2 alopecia were low, a respective 5.9% and 8%, with the combination.
The dose of capecitabine used in the control arm was noted to be higher than that used in usual practice.
“This was because of the global nature of the study and the regulatory requirements globally,” Dr. O’Shaughnessy said.
“The dose-modification scheme was that patients could have a dose reduction at the first sign of grade 2 toxicity,” she added, giving investigators the flexibility to reduce the dose as soon as possible.
This study was sponsored by Odonate Therapeutics. Dr. O’Shaughnessy disclosed consulting fees from AbbVie, Agendia, AstraZeneca, Bristol-Myers Squibb, Celgene, Eisai, Genentech/Roche, Genomic Health, GRAIL, Heron, Immunomedics, Ipsen, Jounce, Lilly, Novartis, Odonate, Pfizer, Puma, and Seagen. Dr. Burstein and Dr. Cardoso had no relevant disclosures.
SOURCE: O’Shaughnessy J et al. SABCS 2020, Abstract GS4-01.
These results suggest tesetaxel plus capecitabine is “a potential new treatment option” for this patient population, said study investigator Joyce O’Shaughnessy, MD, of Baylor University Medical Center and Texas Oncology, both in Dallas.
“This should launch an oral taxane into the clinical space, which will be a nice addition to the toolbox for treating advanced breast cancer, with real upsides for patients,” said Hal Burstein, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, who was not involved in the trial but commented on the results in an interview.
Another commenter was more critical of CONTESSA’s results, which were presented at the 2020 San Antonio Breast Cancer Symposium.
“Three months’ difference in PFS in this setting is meaningless without overall survival [OS] results,” Fatima Cardoso, MD, of Champalimaud Clinical Center in Lisbon, Portugal, said in a question submitted through the virtual meeting’s chat system.
At this point, the OS data are immature, and mature data won’t be available for another couple of years at least, according to the study’s protocol.
Dr. O’Shaughnessy defended the PFS result as being significant, however, saying it was comparable with outcomes seen previously with docetaxel-capecitabine and paclitaxel-gemcitabine combinations.
Other meeting attendees questioned why the waters had been muddied by testing the effects of tesetaxel in combination with capecitabine, albeit at a reduced dose, versus the approved full dose of capecitabine as monotherapy, particularly as a phase 2 trial had shown that tesetaxel demonstrated “significant activity” as monotherapy.
“The reason for the combination versus a monotherapy is because it was designed as a registration trial,” Dr. O’Shaughnessy explained. The trial was designed to be very similar to early taxane studies where docetaxel was assessed with or without capecitabine, or paclitaxel with or without gemcitabine.
“Probably we’re going to be using a doublet for patients who have virulent disease who really need a response,” Dr. O’Shaughnessy explained. She noted that the objective response rate was much higher with the tesetaxel-capecitabine combination than with capecitabine alone, and that result alone is “probably enough that we would utilize a doublet.”
The key thing is that it now gives patients an all-oral option, Dr. O’Shaughnessy said.
“The data are exciting because it would be terrific to have an orally available taxane chemotherapy,” agreed Dr. Burstein. “It is far more convenient for patients and opens access globally in places that do not have adequate resources for administration of IV therapeutics. Also, the data suggest that tesetaxel has a different side effect profile than IV taxane, with less neuropathy and less alopecia.”
Trial design
CONTESSA is an ongoing randomized, controlled trial that started in 2017 and is projected to end in early 2023. It is investigating the use of tesetaxel plus a reduced dose of capecitabine versus the approved dose of capecitabine alone in 685 women with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer who had previously been treated with a taxane.
Being intrinsically orally bioavailable and more soluble than the other taxanes means that tesetaxel has a much longer half-life that allows for a “more convenient treatment experience for patients,” Dr. O’Shaughnessy observed.
Indeed, because tesetaxel only needs to be dosed once every 3 weeks, patients in the trial received tesetaxel at 27 mg/m2 only on the first day of a 21-day treatment cycle. This was combined with a reduced, 825-mg/m2 dose of capecitabine, given orally twice-daily on days 2-14 but once daily on the evening of day 1 and on the morning of day 15.
The combination regimen was compared with the recommended full dose of capecitabine alone, 1,250 mg/m2 given orally twice daily on days 2-14 but once daily on the evening of day 1 and on the morning of day 15.
Efficacy and safety
PFS was 9.8 months with tesetaxel plus capecitabine and 6.9 months with capecitabine alone, representing a 2.9-month improvement with the combination (hazard ratio, 0.716; P = .003).
A similar PFS benefit was seen regardless of multiple predefined subgroups, such as age, baseline performance status, duration of disease-free interval before study entry, and the use of CDK4/6 inhibitors.
The objective response rate was 57% with tesetaxel plus capecitabine and 41% with capecitabine alone (P = .0002). The 24-week disease control rate was 67% and 50%, respectively (P < .0001).
The most frequent treatment-emergent adverse event seen with the tesetaxel-capecitabine combination was neutropenia, occurring in 76.9% of patients, compared with 22.6% of patients in the monotherapy arm. Rates of grade 3-4 neutropenia were much higher in the combination arm (32.6% and 38.3%, respectively) than in the monotherapy arm (7.4% and 0.9%, respectively).
The neutropenia seen was “generally manageable,” Dr. O’Shaughnessy said, primarily with dose reductions and granulocyte colony–stimulating factor as needed.
She pointed out that rates of grade 3 or higher neuropathy and grade 2 alopecia were low, a respective 5.9% and 8%, with the combination.
The dose of capecitabine used in the control arm was noted to be higher than that used in usual practice.
“This was because of the global nature of the study and the regulatory requirements globally,” Dr. O’Shaughnessy said.
“The dose-modification scheme was that patients could have a dose reduction at the first sign of grade 2 toxicity,” she added, giving investigators the flexibility to reduce the dose as soon as possible.
This study was sponsored by Odonate Therapeutics. Dr. O’Shaughnessy disclosed consulting fees from AbbVie, Agendia, AstraZeneca, Bristol-Myers Squibb, Celgene, Eisai, Genentech/Roche, Genomic Health, GRAIL, Heron, Immunomedics, Ipsen, Jounce, Lilly, Novartis, Odonate, Pfizer, Puma, and Seagen. Dr. Burstein and Dr. Cardoso had no relevant disclosures.
SOURCE: O’Shaughnessy J et al. SABCS 2020, Abstract GS4-01.
FROM SABCS 2020
Pembro benefits in mTNBC regardless of chemo type
Adding pembrolizumab to chemotherapy substantially increases progression-free survival (PFS) in treatment-naive advanced or metastatic triple-negative breast cancer (TNBC) regardless of chemotherapy type, suggests an analysis of the clinical trial KEYNOTE-355.
There was also a trend for improved outcomes with increasing programmed death–ligand 1 (PD-L1) expression in the tumor, as measured by combined positive score (CPS).
“These data further support a role for the addition of pembro to standard chemo for the first-line treatment of metastatic TNBC,” said study presenter Hope S. Rugo, MD, from the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.
The research was presented at the 2020 San Antonio Breast Cancer Symposium on Dec. 10.
Last month, pembrolizumab was granted accelerated approval by the Food and Drug Administration in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10).
The approval was based on data from KEYNOTE-355, which involved almost 850 women with previously untreated locally recurrent inoperable or metastatic TNBC randomized 2:1 to pembrolizumab plus investigator’s choice of chemotherapy who were followed for 2 years.
For the current analysis, patients were stratified by PD-L1 CPS in the tumor, including over 320 patients with CPS ≥10, and by accompanying chemotherapy regimen.
In the overall intention-to-treat (ITT) population (n = 847), median PFS was longer with pembrolizumab plus chemotherapy versus placebo plus chemotherapy, at 9.7 months versus 5.6 months (hazard ratio, 0.82).
PFS improved step-wise with increased PD-L1 expression. In patients with PD-L1 CPS ≥1, the HR was 0.74, and in those with PD-L1 CPS ≥10, it was 0.65.
A similar incremental improvement by PD-L1 expression was seen in the overall response rate, with the rate topping out at 53.2% in the pembrolizumab plus chemotherapy arm, among the PD-L1 CPS ≥10 group.
Duration of response told a similar story, with the pembro-chemo combination providing superior results and the treatment effect increasing with PD-L1 enrichment.
Study discussant Sylvia Adams, MD, New York University Perlmutter Cancer Center, New York, said the “consistency of treatment effect” with different chemotherapy backbones seen in the study is “very important, as it is currently unknown what the optimal backbone is.”
She also noted that the chemotherapy analysis presented by Dr. Rugo was “exploratory” and “not powered to show the winner of the chemotherapy backbone.”
Nevertheless, in the postpresentation debate, Ian Krop, MD, PhD, Dana-Farber Cancer Institute, Boston, said that there are “several questions over the chemotherapy partner,” including whether there were differences in the populations who received each type of regimen.
Dr. Rugo replied that “because the trial wasn’t powered to look at the separate chemotherapy groups with any statistical significance ... it’s really impossible to draw any specific conclusions because it’s the overall population that’s evaluated.”
Asked about when overall survival results will be presented, Dr. Rugo said that “everybody is very interested” in that, “and we expect these results to be available next year.”
Study details
For KEYNOTE-355, researchers recruited women with previously untreated metastatic TNBC who had completed treatment with curative intent ≥6 months prior to their first disease recurrence.
They were randomized 2:1 to pembrolizumab or placebo plus investigator’s choice of chemotherapy from nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin for up to 35 administrations of pembrolizumab or placebo or until progression, intolerable toxicity, or cessation of treatment.
Crossover was not allowed. Patients were stratified by type of chemotherapy, PD-L1 expression in the tumor, and prior treatment in the neoadjuvant or adjuvant setting with the same class of chemotherapy.
Response was assessed with imaging every 8 weeks until week 24, then every 9 weeks during the first year of follow-up, and then every 12 weeks.
Of 847 randomized patients, 566 received pembrolizumab plus chemotherapy and 281 were assigned to the placebo group. The median age was 53 years in both groups.
The majority (75.1%) of patients in both groups were PD-L1 positive with a centrally assessed CPS ≥1, while 38.9% of patients in the pembrolizumab arm and 36.7% of those given placebo had a CPS ≥10.
After a median follow-up of 25.9 months, 16 patients given pembrolizumab had completed the study and 33 were still ongoing.
This compares with five patients having completed the placebo arm, and 12 still ongoing, after a median follow-up of 26.3 months.
The overall response rate was higher with pembrolizumab plus chemotherapy in the ITT population, at 41.0% versus 35.9%, rising to 45.2% versus 37.9% in patients with PD-L1 CPS ≥1 and 53.2% versus 39.8% in the PD-L1 CPS ≥10 group.
Again, when the groups were stratified by on-study chemotherapy, the overall response rate was higher with pembrolizumab versus placebo regardless of the chemotherapy partner.
Finally, the duration of response with pembrolizumab plus chemotherapy was longer than that seen with placebo, at a median of 10.1 months versus 6.4 months in the ITT population.
In the PD-L1 CPS ≥1 group, the duration of response was 10.1 months versus 6.5 months, rising to 19.3 months versus 7.3 months in the PD-L1 CPS ≥10 group.
Dr. Adams nevertheless said that PD-L1 remains an “imperfect” biomarker in metastatic TNBC, although it is “the best to date.” Furthermore, the IMpassion130 trial, featuring atezolizumab, showed that there is “very poor” analytic and clinical concordance between assays, which “complicates clinical decision-making.”
This study was sponsored by Merck. Dr. Rugo, Dr. Adams, and Dr. Krop have disclosed financial ties to multiple pharmaceutical companies, including Merck.
A version of this article first appeared on Medscape.com.
Adding pembrolizumab to chemotherapy substantially increases progression-free survival (PFS) in treatment-naive advanced or metastatic triple-negative breast cancer (TNBC) regardless of chemotherapy type, suggests an analysis of the clinical trial KEYNOTE-355.
There was also a trend for improved outcomes with increasing programmed death–ligand 1 (PD-L1) expression in the tumor, as measured by combined positive score (CPS).
“These data further support a role for the addition of pembro to standard chemo for the first-line treatment of metastatic TNBC,” said study presenter Hope S. Rugo, MD, from the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.
The research was presented at the 2020 San Antonio Breast Cancer Symposium on Dec. 10.
Last month, pembrolizumab was granted accelerated approval by the Food and Drug Administration in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10).
The approval was based on data from KEYNOTE-355, which involved almost 850 women with previously untreated locally recurrent inoperable or metastatic TNBC randomized 2:1 to pembrolizumab plus investigator’s choice of chemotherapy who were followed for 2 years.
For the current analysis, patients were stratified by PD-L1 CPS in the tumor, including over 320 patients with CPS ≥10, and by accompanying chemotherapy regimen.
In the overall intention-to-treat (ITT) population (n = 847), median PFS was longer with pembrolizumab plus chemotherapy versus placebo plus chemotherapy, at 9.7 months versus 5.6 months (hazard ratio, 0.82).
PFS improved step-wise with increased PD-L1 expression. In patients with PD-L1 CPS ≥1, the HR was 0.74, and in those with PD-L1 CPS ≥10, it was 0.65.
A similar incremental improvement by PD-L1 expression was seen in the overall response rate, with the rate topping out at 53.2% in the pembrolizumab plus chemotherapy arm, among the PD-L1 CPS ≥10 group.
Duration of response told a similar story, with the pembro-chemo combination providing superior results and the treatment effect increasing with PD-L1 enrichment.
Study discussant Sylvia Adams, MD, New York University Perlmutter Cancer Center, New York, said the “consistency of treatment effect” with different chemotherapy backbones seen in the study is “very important, as it is currently unknown what the optimal backbone is.”
She also noted that the chemotherapy analysis presented by Dr. Rugo was “exploratory” and “not powered to show the winner of the chemotherapy backbone.”
Nevertheless, in the postpresentation debate, Ian Krop, MD, PhD, Dana-Farber Cancer Institute, Boston, said that there are “several questions over the chemotherapy partner,” including whether there were differences in the populations who received each type of regimen.
Dr. Rugo replied that “because the trial wasn’t powered to look at the separate chemotherapy groups with any statistical significance ... it’s really impossible to draw any specific conclusions because it’s the overall population that’s evaluated.”
Asked about when overall survival results will be presented, Dr. Rugo said that “everybody is very interested” in that, “and we expect these results to be available next year.”
Study details
For KEYNOTE-355, researchers recruited women with previously untreated metastatic TNBC who had completed treatment with curative intent ≥6 months prior to their first disease recurrence.
They were randomized 2:1 to pembrolizumab or placebo plus investigator’s choice of chemotherapy from nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin for up to 35 administrations of pembrolizumab or placebo or until progression, intolerable toxicity, or cessation of treatment.
Crossover was not allowed. Patients were stratified by type of chemotherapy, PD-L1 expression in the tumor, and prior treatment in the neoadjuvant or adjuvant setting with the same class of chemotherapy.
Response was assessed with imaging every 8 weeks until week 24, then every 9 weeks during the first year of follow-up, and then every 12 weeks.
Of 847 randomized patients, 566 received pembrolizumab plus chemotherapy and 281 were assigned to the placebo group. The median age was 53 years in both groups.
The majority (75.1%) of patients in both groups were PD-L1 positive with a centrally assessed CPS ≥1, while 38.9% of patients in the pembrolizumab arm and 36.7% of those given placebo had a CPS ≥10.
After a median follow-up of 25.9 months, 16 patients given pembrolizumab had completed the study and 33 were still ongoing.
This compares with five patients having completed the placebo arm, and 12 still ongoing, after a median follow-up of 26.3 months.
The overall response rate was higher with pembrolizumab plus chemotherapy in the ITT population, at 41.0% versus 35.9%, rising to 45.2% versus 37.9% in patients with PD-L1 CPS ≥1 and 53.2% versus 39.8% in the PD-L1 CPS ≥10 group.
Again, when the groups were stratified by on-study chemotherapy, the overall response rate was higher with pembrolizumab versus placebo regardless of the chemotherapy partner.
Finally, the duration of response with pembrolizumab plus chemotherapy was longer than that seen with placebo, at a median of 10.1 months versus 6.4 months in the ITT population.
In the PD-L1 CPS ≥1 group, the duration of response was 10.1 months versus 6.5 months, rising to 19.3 months versus 7.3 months in the PD-L1 CPS ≥10 group.
Dr. Adams nevertheless said that PD-L1 remains an “imperfect” biomarker in metastatic TNBC, although it is “the best to date.” Furthermore, the IMpassion130 trial, featuring atezolizumab, showed that there is “very poor” analytic and clinical concordance between assays, which “complicates clinical decision-making.”
This study was sponsored by Merck. Dr. Rugo, Dr. Adams, and Dr. Krop have disclosed financial ties to multiple pharmaceutical companies, including Merck.
A version of this article first appeared on Medscape.com.
Adding pembrolizumab to chemotherapy substantially increases progression-free survival (PFS) in treatment-naive advanced or metastatic triple-negative breast cancer (TNBC) regardless of chemotherapy type, suggests an analysis of the clinical trial KEYNOTE-355.
There was also a trend for improved outcomes with increasing programmed death–ligand 1 (PD-L1) expression in the tumor, as measured by combined positive score (CPS).
“These data further support a role for the addition of pembro to standard chemo for the first-line treatment of metastatic TNBC,” said study presenter Hope S. Rugo, MD, from the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.
The research was presented at the 2020 San Antonio Breast Cancer Symposium on Dec. 10.
Last month, pembrolizumab was granted accelerated approval by the Food and Drug Administration in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10).
The approval was based on data from KEYNOTE-355, which involved almost 850 women with previously untreated locally recurrent inoperable or metastatic TNBC randomized 2:1 to pembrolizumab plus investigator’s choice of chemotherapy who were followed for 2 years.
For the current analysis, patients were stratified by PD-L1 CPS in the tumor, including over 320 patients with CPS ≥10, and by accompanying chemotherapy regimen.
In the overall intention-to-treat (ITT) population (n = 847), median PFS was longer with pembrolizumab plus chemotherapy versus placebo plus chemotherapy, at 9.7 months versus 5.6 months (hazard ratio, 0.82).
PFS improved step-wise with increased PD-L1 expression. In patients with PD-L1 CPS ≥1, the HR was 0.74, and in those with PD-L1 CPS ≥10, it was 0.65.
A similar incremental improvement by PD-L1 expression was seen in the overall response rate, with the rate topping out at 53.2% in the pembrolizumab plus chemotherapy arm, among the PD-L1 CPS ≥10 group.
Duration of response told a similar story, with the pembro-chemo combination providing superior results and the treatment effect increasing with PD-L1 enrichment.
Study discussant Sylvia Adams, MD, New York University Perlmutter Cancer Center, New York, said the “consistency of treatment effect” with different chemotherapy backbones seen in the study is “very important, as it is currently unknown what the optimal backbone is.”
She also noted that the chemotherapy analysis presented by Dr. Rugo was “exploratory” and “not powered to show the winner of the chemotherapy backbone.”
Nevertheless, in the postpresentation debate, Ian Krop, MD, PhD, Dana-Farber Cancer Institute, Boston, said that there are “several questions over the chemotherapy partner,” including whether there were differences in the populations who received each type of regimen.
Dr. Rugo replied that “because the trial wasn’t powered to look at the separate chemotherapy groups with any statistical significance ... it’s really impossible to draw any specific conclusions because it’s the overall population that’s evaluated.”
Asked about when overall survival results will be presented, Dr. Rugo said that “everybody is very interested” in that, “and we expect these results to be available next year.”
Study details
For KEYNOTE-355, researchers recruited women with previously untreated metastatic TNBC who had completed treatment with curative intent ≥6 months prior to their first disease recurrence.
They were randomized 2:1 to pembrolizumab or placebo plus investigator’s choice of chemotherapy from nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin for up to 35 administrations of pembrolizumab or placebo or until progression, intolerable toxicity, or cessation of treatment.
Crossover was not allowed. Patients were stratified by type of chemotherapy, PD-L1 expression in the tumor, and prior treatment in the neoadjuvant or adjuvant setting with the same class of chemotherapy.
Response was assessed with imaging every 8 weeks until week 24, then every 9 weeks during the first year of follow-up, and then every 12 weeks.
Of 847 randomized patients, 566 received pembrolizumab plus chemotherapy and 281 were assigned to the placebo group. The median age was 53 years in both groups.
The majority (75.1%) of patients in both groups were PD-L1 positive with a centrally assessed CPS ≥1, while 38.9% of patients in the pembrolizumab arm and 36.7% of those given placebo had a CPS ≥10.
After a median follow-up of 25.9 months, 16 patients given pembrolizumab had completed the study and 33 were still ongoing.
This compares with five patients having completed the placebo arm, and 12 still ongoing, after a median follow-up of 26.3 months.
The overall response rate was higher with pembrolizumab plus chemotherapy in the ITT population, at 41.0% versus 35.9%, rising to 45.2% versus 37.9% in patients with PD-L1 CPS ≥1 and 53.2% versus 39.8% in the PD-L1 CPS ≥10 group.
Again, when the groups were stratified by on-study chemotherapy, the overall response rate was higher with pembrolizumab versus placebo regardless of the chemotherapy partner.
Finally, the duration of response with pembrolizumab plus chemotherapy was longer than that seen with placebo, at a median of 10.1 months versus 6.4 months in the ITT population.
In the PD-L1 CPS ≥1 group, the duration of response was 10.1 months versus 6.5 months, rising to 19.3 months versus 7.3 months in the PD-L1 CPS ≥10 group.
Dr. Adams nevertheless said that PD-L1 remains an “imperfect” biomarker in metastatic TNBC, although it is “the best to date.” Furthermore, the IMpassion130 trial, featuring atezolizumab, showed that there is “very poor” analytic and clinical concordance between assays, which “complicates clinical decision-making.”
This study was sponsored by Merck. Dr. Rugo, Dr. Adams, and Dr. Krop have disclosed financial ties to multiple pharmaceutical companies, including Merck.
A version of this article first appeared on Medscape.com.
First-in-class ADC has benefit across mTNBC subgroups
But both an observer and the lead study author cautioned that the results were hypothesis generating.
Nonetheless, the data suggest the drug yields good survival outcomes in comparison with placebo in both BRCA1/2-positive and -negative patients and is effective even for those with low expression of the target protein, trophoblast cell surface antigen 2 (Trop-2).
The research was presented at the San Antonio Breast Cancer Symposium (SABCS) 2020.
Study presenter Sara Hurvitz, MD, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, urged caution in interpreting the data, given the small sample sizes in the Trop-2–low subgroup and germline BRCA1/2-positive subgroup.
Jennifer K. Litton, MD, University of Texas MD Anderson Cancer Center, Houston, Texas, who was not involved in the research, echoed those comments.
She told Medscape Medical News that the numbers, particularly for the BRCA1/2 analysis, were “very small.”
She added: “This was not a prespecified group, so it represents an interesting analysis to be hypothesis generating for future studies but not anything applicable to current clinical practice.”
Nevertheless, Litton said the data from the primary analysis of ASCENT remain “practice changing” for women with mTNBC who have received at least two previous lines of therapy.
As to whether SG will eventually move beyond this advanced setting, she emphasized that “more trials would need to be done and reported evaluating its role in other settings, and hopefully expanding its usefulness for patients.”
SG is a first-in-class drug comprising an antibody directed at Trop-2, which is highly expressed in breast cancer, and linked to SN-38, the active metabolite of irinotecan.
On the basis of positive phase 1/2 trial data, SG was granted accelerated approval by the US Food and Drug Administration for patients with mTNBC who experience disease progression after at least two prior therapies.
As reported by Medscape Medical News, primary results from ASCENT that were presented at ESMO 2020 showed that SG improved progression-free survival (PFS) by nearly 4 months and overall survival by more than 5 months for women with pretreated mTNBC compared to chemotherapy.
Study details
At SABCS, Hurvitz presented an exploratory biomarker evaluation of data from the trial regarding the association between SG efficacy and Trop-2 expression, as well as germline BRCA1/2 mutation status.
She reminded the audience that, in ASCENT, 529 patients with mTNBC who had experienced disease progression after undergoing at least two chemotherapy regimens for advanced disease were randomly assigned in a 1:1 ratio to receive intravenous SG on days 1 and 8 of a 21-day cycle or physician’s choice of treatment.
Treatment was continued until disease progression or unacceptable toxicity occurred.
For the current analysis, which focused on patients who did not have brain metastases, the team studied primary or metastatic archival biopsy or surgical specimens collected at study entry.
These were analyzed using a validated immunohistochemistry assay. Tumors were categorized as Trop-2–low, –medium, or –-high expressers on the basis of H-score, which is a weighted summation of percent staining. In addition, germline BRCA1/2 mutation status was determined at baseline.
Mutation status was known for 149 SG patients and 143 control patients. Of those, the majority (57% and 54%, respectively) were BRCA1/2 negative.
Among 151 SG patients for whom Trop-2 expression status was available, 56% had tumors of high expression; 26%, medium expression; and 18%, low expression. In the control group, Trop-2 expression was known in 139 patients, of whom 52% had tumors of high expression; 25%, medium expression; and 23%, low expression.
Hurvitz reported that, although median PFS among patients given SG decreased with decreasing Trop-2 expression, it remained longer than that seen with control treatment. In patients with tumors of Trop-2–high status, median PFS was 6.9 months with SG, vs. 2.5 for patients who underwent control treatment. This fell to 5.6 months vs. 2.2 months in the Trop-2–medium group and 2.7 months vs 1.6 months in Trop-2–low group.
A similar pattern was seen for overall survival. In the Trop-2–high group, median overall survival was 14.2 months with SG, vs. 6.9 months with control therapy; 14.9 months vs. 6.9 months in the Trop-2–medium group; and 9.3 months vs. 7.6 months in the Trop-2–low group.
Again, the objective response rate fell from 44% to 38% and then to 22% with SG in the Trop-2–high, –medium, and –low groups, compared with 1%, 11%, and 6%, respectively, with control treatment.
There did not seem to be any interaction between Trop-2 expression and treatment-related adverse events of special interest. Rates of neutropenia, diarrhea, and anemia were consistently higher in SG-treated patients than in those given placebo.
Hurvitz said the objective response rate was markedly higher with SG vs. control treatment in both BRCA1/2-positive and -negative patients, at 19% vs. 6% in the positive group and 33% vs. 6% in the negative group.
This was reflected in improved median PFS with SG in both subgroups, at 4.6 months vs. 2.5 months with control therapy in BRCA1/2-positive patients and 4.9 months vs. 1.6 months in BRCA1/2-negative patients.
Overall survival was 15.6 months with SG, vs. 4.4 months with control treatment in BRCA1/2-positive patients. In BRCA1/2-negative patients, the respective figures were 10.9 months and 7.0 months.
The study was sponsored by Immunomedics. Hurvitz has financial ties to Immunomedics and multiple other pharmaceutical companies. Litton has financial ties to multiple companies, including Medscape and companies developing and marketing breast cancer therapies.
This article first appeared on Medscape.com.
But both an observer and the lead study author cautioned that the results were hypothesis generating.
Nonetheless, the data suggest the drug yields good survival outcomes in comparison with placebo in both BRCA1/2-positive and -negative patients and is effective even for those with low expression of the target protein, trophoblast cell surface antigen 2 (Trop-2).
The research was presented at the San Antonio Breast Cancer Symposium (SABCS) 2020.
Study presenter Sara Hurvitz, MD, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, urged caution in interpreting the data, given the small sample sizes in the Trop-2–low subgroup and germline BRCA1/2-positive subgroup.
Jennifer K. Litton, MD, University of Texas MD Anderson Cancer Center, Houston, Texas, who was not involved in the research, echoed those comments.
She told Medscape Medical News that the numbers, particularly for the BRCA1/2 analysis, were “very small.”
She added: “This was not a prespecified group, so it represents an interesting analysis to be hypothesis generating for future studies but not anything applicable to current clinical practice.”
Nevertheless, Litton said the data from the primary analysis of ASCENT remain “practice changing” for women with mTNBC who have received at least two previous lines of therapy.
As to whether SG will eventually move beyond this advanced setting, she emphasized that “more trials would need to be done and reported evaluating its role in other settings, and hopefully expanding its usefulness for patients.”
SG is a first-in-class drug comprising an antibody directed at Trop-2, which is highly expressed in breast cancer, and linked to SN-38, the active metabolite of irinotecan.
On the basis of positive phase 1/2 trial data, SG was granted accelerated approval by the US Food and Drug Administration for patients with mTNBC who experience disease progression after at least two prior therapies.
As reported by Medscape Medical News, primary results from ASCENT that were presented at ESMO 2020 showed that SG improved progression-free survival (PFS) by nearly 4 months and overall survival by more than 5 months for women with pretreated mTNBC compared to chemotherapy.
Study details
At SABCS, Hurvitz presented an exploratory biomarker evaluation of data from the trial regarding the association between SG efficacy and Trop-2 expression, as well as germline BRCA1/2 mutation status.
She reminded the audience that, in ASCENT, 529 patients with mTNBC who had experienced disease progression after undergoing at least two chemotherapy regimens for advanced disease were randomly assigned in a 1:1 ratio to receive intravenous SG on days 1 and 8 of a 21-day cycle or physician’s choice of treatment.
Treatment was continued until disease progression or unacceptable toxicity occurred.
For the current analysis, which focused on patients who did not have brain metastases, the team studied primary or metastatic archival biopsy or surgical specimens collected at study entry.
These were analyzed using a validated immunohistochemistry assay. Tumors were categorized as Trop-2–low, –medium, or –-high expressers on the basis of H-score, which is a weighted summation of percent staining. In addition, germline BRCA1/2 mutation status was determined at baseline.
Mutation status was known for 149 SG patients and 143 control patients. Of those, the majority (57% and 54%, respectively) were BRCA1/2 negative.
Among 151 SG patients for whom Trop-2 expression status was available, 56% had tumors of high expression; 26%, medium expression; and 18%, low expression. In the control group, Trop-2 expression was known in 139 patients, of whom 52% had tumors of high expression; 25%, medium expression; and 23%, low expression.
Hurvitz reported that, although median PFS among patients given SG decreased with decreasing Trop-2 expression, it remained longer than that seen with control treatment. In patients with tumors of Trop-2–high status, median PFS was 6.9 months with SG, vs. 2.5 for patients who underwent control treatment. This fell to 5.6 months vs. 2.2 months in the Trop-2–medium group and 2.7 months vs 1.6 months in Trop-2–low group.
A similar pattern was seen for overall survival. In the Trop-2–high group, median overall survival was 14.2 months with SG, vs. 6.9 months with control therapy; 14.9 months vs. 6.9 months in the Trop-2–medium group; and 9.3 months vs. 7.6 months in the Trop-2–low group.
Again, the objective response rate fell from 44% to 38% and then to 22% with SG in the Trop-2–high, –medium, and –low groups, compared with 1%, 11%, and 6%, respectively, with control treatment.
There did not seem to be any interaction between Trop-2 expression and treatment-related adverse events of special interest. Rates of neutropenia, diarrhea, and anemia were consistently higher in SG-treated patients than in those given placebo.
Hurvitz said the objective response rate was markedly higher with SG vs. control treatment in both BRCA1/2-positive and -negative patients, at 19% vs. 6% in the positive group and 33% vs. 6% in the negative group.
This was reflected in improved median PFS with SG in both subgroups, at 4.6 months vs. 2.5 months with control therapy in BRCA1/2-positive patients and 4.9 months vs. 1.6 months in BRCA1/2-negative patients.
Overall survival was 15.6 months with SG, vs. 4.4 months with control treatment in BRCA1/2-positive patients. In BRCA1/2-negative patients, the respective figures were 10.9 months and 7.0 months.
The study was sponsored by Immunomedics. Hurvitz has financial ties to Immunomedics and multiple other pharmaceutical companies. Litton has financial ties to multiple companies, including Medscape and companies developing and marketing breast cancer therapies.
This article first appeared on Medscape.com.
But both an observer and the lead study author cautioned that the results were hypothesis generating.
Nonetheless, the data suggest the drug yields good survival outcomes in comparison with placebo in both BRCA1/2-positive and -negative patients and is effective even for those with low expression of the target protein, trophoblast cell surface antigen 2 (Trop-2).
The research was presented at the San Antonio Breast Cancer Symposium (SABCS) 2020.
Study presenter Sara Hurvitz, MD, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, urged caution in interpreting the data, given the small sample sizes in the Trop-2–low subgroup and germline BRCA1/2-positive subgroup.
Jennifer K. Litton, MD, University of Texas MD Anderson Cancer Center, Houston, Texas, who was not involved in the research, echoed those comments.
She told Medscape Medical News that the numbers, particularly for the BRCA1/2 analysis, were “very small.”
She added: “This was not a prespecified group, so it represents an interesting analysis to be hypothesis generating for future studies but not anything applicable to current clinical practice.”
Nevertheless, Litton said the data from the primary analysis of ASCENT remain “practice changing” for women with mTNBC who have received at least two previous lines of therapy.
As to whether SG will eventually move beyond this advanced setting, she emphasized that “more trials would need to be done and reported evaluating its role in other settings, and hopefully expanding its usefulness for patients.”
SG is a first-in-class drug comprising an antibody directed at Trop-2, which is highly expressed in breast cancer, and linked to SN-38, the active metabolite of irinotecan.
On the basis of positive phase 1/2 trial data, SG was granted accelerated approval by the US Food and Drug Administration for patients with mTNBC who experience disease progression after at least two prior therapies.
As reported by Medscape Medical News, primary results from ASCENT that were presented at ESMO 2020 showed that SG improved progression-free survival (PFS) by nearly 4 months and overall survival by more than 5 months for women with pretreated mTNBC compared to chemotherapy.
Study details
At SABCS, Hurvitz presented an exploratory biomarker evaluation of data from the trial regarding the association between SG efficacy and Trop-2 expression, as well as germline BRCA1/2 mutation status.
She reminded the audience that, in ASCENT, 529 patients with mTNBC who had experienced disease progression after undergoing at least two chemotherapy regimens for advanced disease were randomly assigned in a 1:1 ratio to receive intravenous SG on days 1 and 8 of a 21-day cycle or physician’s choice of treatment.
Treatment was continued until disease progression or unacceptable toxicity occurred.
For the current analysis, which focused on patients who did not have brain metastases, the team studied primary or metastatic archival biopsy or surgical specimens collected at study entry.
These were analyzed using a validated immunohistochemistry assay. Tumors were categorized as Trop-2–low, –medium, or –-high expressers on the basis of H-score, which is a weighted summation of percent staining. In addition, germline BRCA1/2 mutation status was determined at baseline.
Mutation status was known for 149 SG patients and 143 control patients. Of those, the majority (57% and 54%, respectively) were BRCA1/2 negative.
Among 151 SG patients for whom Trop-2 expression status was available, 56% had tumors of high expression; 26%, medium expression; and 18%, low expression. In the control group, Trop-2 expression was known in 139 patients, of whom 52% had tumors of high expression; 25%, medium expression; and 23%, low expression.
Hurvitz reported that, although median PFS among patients given SG decreased with decreasing Trop-2 expression, it remained longer than that seen with control treatment. In patients with tumors of Trop-2–high status, median PFS was 6.9 months with SG, vs. 2.5 for patients who underwent control treatment. This fell to 5.6 months vs. 2.2 months in the Trop-2–medium group and 2.7 months vs 1.6 months in Trop-2–low group.
A similar pattern was seen for overall survival. In the Trop-2–high group, median overall survival was 14.2 months with SG, vs. 6.9 months with control therapy; 14.9 months vs. 6.9 months in the Trop-2–medium group; and 9.3 months vs. 7.6 months in the Trop-2–low group.
Again, the objective response rate fell from 44% to 38% and then to 22% with SG in the Trop-2–high, –medium, and –low groups, compared with 1%, 11%, and 6%, respectively, with control treatment.
There did not seem to be any interaction between Trop-2 expression and treatment-related adverse events of special interest. Rates of neutropenia, diarrhea, and anemia were consistently higher in SG-treated patients than in those given placebo.
Hurvitz said the objective response rate was markedly higher with SG vs. control treatment in both BRCA1/2-positive and -negative patients, at 19% vs. 6% in the positive group and 33% vs. 6% in the negative group.
This was reflected in improved median PFS with SG in both subgroups, at 4.6 months vs. 2.5 months with control therapy in BRCA1/2-positive patients and 4.9 months vs. 1.6 months in BRCA1/2-negative patients.
Overall survival was 15.6 months with SG, vs. 4.4 months with control treatment in BRCA1/2-positive patients. In BRCA1/2-negative patients, the respective figures were 10.9 months and 7.0 months.
The study was sponsored by Immunomedics. Hurvitz has financial ties to Immunomedics and multiple other pharmaceutical companies. Litton has financial ties to multiple companies, including Medscape and companies developing and marketing breast cancer therapies.
This article first appeared on Medscape.com.
FROM SABCS 2020
Adding atezolizumab to chemo doesn’t worsen QOL in early TNBC
In the randomized phase 3 trial, patients received neoadjuvant atezolizumab or placebo plus chemotherapy, followed by surgery and adjuvant atezolizumab or observation.
An analysis of patient-reported outcomes showed that, after a brief decline in health-related quality of life (HRQOL) in both the atezolizumab and control arms, the burden of treatment eased and then remained similar throughout follow-up.
“Treatment-related symptoms in both arms were similar, and the addition of atezolizumab to chemotherapy was tolerable, with no additional treatment side-effect bother reported,” said Elizabeth Mittendorf, MD, PhD, of the Dana-Farber Cancer Institute in Boston.
She presented these results in an oral abstract presentation during the 2020 San Antonio Breast Cancer Symposium.
Initial results
Primary results of the IMpassion031 trial were reported at ESMO 2020 and published in The Lancet.
The trial enrolled patients with treatment-naive early TNBC, and they were randomized to receive chemotherapy plus atezolizumab or placebo. Atezolizumab was given at 840 mg intravenously every 2 weeks.
Chemotherapy consisted of nab-paclitaxel at 125 mg/m2 every week for 12 weeks followed by doxorubicin at 60 mg/m2 and cyclophosphamide at 600 mg/m2 every 2 weeks for 8 weeks. Patients then underwent surgery, which was followed by either atezolizumab maintenance or observation.
The addition of atezolizumab was associated with a 17% improvement in the rate of pathological complete response (pCR) in the intention-to-treat population.
Among patients positive for PD-L1, atezolizumab was associated with a 20% improvement in pCR rate.
Patients have their say
At SABCS 2020, Dr. Mittendorf presented patient-reported outcomes (PRO) for 161 patients randomized to atezolizumab plus chemotherapy and 167 assigned to placebo plus chemotherapy.
The outcome measures – including role function (the ability to work or pursue common everyday activities), physical function, emotional and social function, and HRQOL – came from scores on the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30).
The exploratory PRO endpoints were mean function and disease- or treatment-related symptoms as well as mean change from baseline in these symptoms.
At baseline, mean physical function scores were high in both arms, at approximately 90%. They dropped to about 65% in each arm by cycle 5 and rebounded to about 80% by cycle 7.
“The change was clinically meaningful, in that the dip was greater than 10 points,” Dr. Mittendorf said. “As patients completed neoadjuvant therapy and were in the adjuvant phase of the study, there was an increase and stabilization with respect to their physical function.”
Similarly, role function declined from 89% in each arm at baseline to a nadir of about 55% in the placebo arm and 50% in the atezolizumab arm. After cycle 5, role function levels began to increase in both arms and remained above 70% from cycle 7 onward.
Role function did not completely recover or stabilize among patients in the atezolizumab arm, “and we attribute this to the fact that these patients continue to receive atezolizumab, which requires that they come to clinic for that therapy, thereby potentially impacting role function,” Dr. Mittendorf said.
She reported that HRQOL declined from a median of nearly 80% at baseline in both arms to a nadir of 62% in the placebo arm and 52% in the atezolizumab arm by cycle 5. HRQOL rebounded starting at cycle 6 and stabilized thereafter, with little daylight between the treatment arms at the most recent follow-up.
The investigators saw worsening of the treatment-related symptoms fatigue, nausea/vomiting, and diarrhea in each arm, with the highest level of symptoms except pain reported at cycle 5. The highest reported pain level was seen at cycle 4.
In each arm, the symptoms declined and stabilized in the adjuvant setting, with mean values at week 16 similar to those reported at baseline for most symptoms. The exception was fatigue, which remained slightly elevated in both arms.
Regarding side-effect bother, a similar proportion of patients in each arm reported increased level of bother by visit during the neoadjuvant phase. However, no additional side-effect bother was reported by patients receiving maintenance atezolizumab, compared with patients in the placebo arm, who were followed with observation alone.
‘Reassuring’ data
“What we can conclude from the PRO in IMpassion031 is that early breast cancer patients are relatively asymptomatic. They do have a good baseline quality of life and very good functioning. The neoadjuvant therapy certainly has deterioration in quality of life and functioning, but this is transient, and there was no evident burden from the atezolizumab,” said invited discussant Sylvia Adams, MD, of New York University.
She said it’s reassuring to see the addition of atezolizumab did not adversely affect HRQOL but added that the study “also shows that chemotherapy has a major impact on well-being, as expected.”
Questions and problems that still need to be addressed regarding the use of immunotherapies in early TNBC include whether every patient needs chemotherapy or immunotherapy, a lack of predictive biomarkers, whether increases in pCR rates after neoadjuvant immunotherapy and chemotherapy will translate into improved survival, and the optimal chemotherapy backbone and schedule, she said.
IMpassion031 is sponsored by F. Hoffman-LaRoche. Dr. Mittendorf disclosed relationships with Roche/Genentech, GlaxoSmithKline, Physicians’ Education Resource, AstraZeneca, Exact Sciences, Merck, Peregrine Pharmaceuticals, SELLAS Life Sciences, TapImmune, EMD Serono, Galena Biopharma, Bristol Myers Squibb, and Lilly. Dr. Adams disclosed relationships with Genentech, Bristol Myers Squibb, Merck, Amgen, Celgene, and Novartis.
SOURCE: Mittendorf E at al. SABCS 2020, Abstract GS3-02.
In the randomized phase 3 trial, patients received neoadjuvant atezolizumab or placebo plus chemotherapy, followed by surgery and adjuvant atezolizumab or observation.
An analysis of patient-reported outcomes showed that, after a brief decline in health-related quality of life (HRQOL) in both the atezolizumab and control arms, the burden of treatment eased and then remained similar throughout follow-up.
“Treatment-related symptoms in both arms were similar, and the addition of atezolizumab to chemotherapy was tolerable, with no additional treatment side-effect bother reported,” said Elizabeth Mittendorf, MD, PhD, of the Dana-Farber Cancer Institute in Boston.
She presented these results in an oral abstract presentation during the 2020 San Antonio Breast Cancer Symposium.
Initial results
Primary results of the IMpassion031 trial were reported at ESMO 2020 and published in The Lancet.
The trial enrolled patients with treatment-naive early TNBC, and they were randomized to receive chemotherapy plus atezolizumab or placebo. Atezolizumab was given at 840 mg intravenously every 2 weeks.
Chemotherapy consisted of nab-paclitaxel at 125 mg/m2 every week for 12 weeks followed by doxorubicin at 60 mg/m2 and cyclophosphamide at 600 mg/m2 every 2 weeks for 8 weeks. Patients then underwent surgery, which was followed by either atezolizumab maintenance or observation.
The addition of atezolizumab was associated with a 17% improvement in the rate of pathological complete response (pCR) in the intention-to-treat population.
Among patients positive for PD-L1, atezolizumab was associated with a 20% improvement in pCR rate.
Patients have their say
At SABCS 2020, Dr. Mittendorf presented patient-reported outcomes (PRO) for 161 patients randomized to atezolizumab plus chemotherapy and 167 assigned to placebo plus chemotherapy.
The outcome measures – including role function (the ability to work or pursue common everyday activities), physical function, emotional and social function, and HRQOL – came from scores on the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30).
The exploratory PRO endpoints were mean function and disease- or treatment-related symptoms as well as mean change from baseline in these symptoms.
At baseline, mean physical function scores were high in both arms, at approximately 90%. They dropped to about 65% in each arm by cycle 5 and rebounded to about 80% by cycle 7.
“The change was clinically meaningful, in that the dip was greater than 10 points,” Dr. Mittendorf said. “As patients completed neoadjuvant therapy and were in the adjuvant phase of the study, there was an increase and stabilization with respect to their physical function.”
Similarly, role function declined from 89% in each arm at baseline to a nadir of about 55% in the placebo arm and 50% in the atezolizumab arm. After cycle 5, role function levels began to increase in both arms and remained above 70% from cycle 7 onward.
Role function did not completely recover or stabilize among patients in the atezolizumab arm, “and we attribute this to the fact that these patients continue to receive atezolizumab, which requires that they come to clinic for that therapy, thereby potentially impacting role function,” Dr. Mittendorf said.
She reported that HRQOL declined from a median of nearly 80% at baseline in both arms to a nadir of 62% in the placebo arm and 52% in the atezolizumab arm by cycle 5. HRQOL rebounded starting at cycle 6 and stabilized thereafter, with little daylight between the treatment arms at the most recent follow-up.
The investigators saw worsening of the treatment-related symptoms fatigue, nausea/vomiting, and diarrhea in each arm, with the highest level of symptoms except pain reported at cycle 5. The highest reported pain level was seen at cycle 4.
In each arm, the symptoms declined and stabilized in the adjuvant setting, with mean values at week 16 similar to those reported at baseline for most symptoms. The exception was fatigue, which remained slightly elevated in both arms.
Regarding side-effect bother, a similar proportion of patients in each arm reported increased level of bother by visit during the neoadjuvant phase. However, no additional side-effect bother was reported by patients receiving maintenance atezolizumab, compared with patients in the placebo arm, who were followed with observation alone.
‘Reassuring’ data
“What we can conclude from the PRO in IMpassion031 is that early breast cancer patients are relatively asymptomatic. They do have a good baseline quality of life and very good functioning. The neoadjuvant therapy certainly has deterioration in quality of life and functioning, but this is transient, and there was no evident burden from the atezolizumab,” said invited discussant Sylvia Adams, MD, of New York University.
She said it’s reassuring to see the addition of atezolizumab did not adversely affect HRQOL but added that the study “also shows that chemotherapy has a major impact on well-being, as expected.”
Questions and problems that still need to be addressed regarding the use of immunotherapies in early TNBC include whether every patient needs chemotherapy or immunotherapy, a lack of predictive biomarkers, whether increases in pCR rates after neoadjuvant immunotherapy and chemotherapy will translate into improved survival, and the optimal chemotherapy backbone and schedule, she said.
IMpassion031 is sponsored by F. Hoffman-LaRoche. Dr. Mittendorf disclosed relationships with Roche/Genentech, GlaxoSmithKline, Physicians’ Education Resource, AstraZeneca, Exact Sciences, Merck, Peregrine Pharmaceuticals, SELLAS Life Sciences, TapImmune, EMD Serono, Galena Biopharma, Bristol Myers Squibb, and Lilly. Dr. Adams disclosed relationships with Genentech, Bristol Myers Squibb, Merck, Amgen, Celgene, and Novartis.
SOURCE: Mittendorf E at al. SABCS 2020, Abstract GS3-02.
In the randomized phase 3 trial, patients received neoadjuvant atezolizumab or placebo plus chemotherapy, followed by surgery and adjuvant atezolizumab or observation.
An analysis of patient-reported outcomes showed that, after a brief decline in health-related quality of life (HRQOL) in both the atezolizumab and control arms, the burden of treatment eased and then remained similar throughout follow-up.
“Treatment-related symptoms in both arms were similar, and the addition of atezolizumab to chemotherapy was tolerable, with no additional treatment side-effect bother reported,” said Elizabeth Mittendorf, MD, PhD, of the Dana-Farber Cancer Institute in Boston.
She presented these results in an oral abstract presentation during the 2020 San Antonio Breast Cancer Symposium.
Initial results
Primary results of the IMpassion031 trial were reported at ESMO 2020 and published in The Lancet.
The trial enrolled patients with treatment-naive early TNBC, and they were randomized to receive chemotherapy plus atezolizumab or placebo. Atezolizumab was given at 840 mg intravenously every 2 weeks.
Chemotherapy consisted of nab-paclitaxel at 125 mg/m2 every week for 12 weeks followed by doxorubicin at 60 mg/m2 and cyclophosphamide at 600 mg/m2 every 2 weeks for 8 weeks. Patients then underwent surgery, which was followed by either atezolizumab maintenance or observation.
The addition of atezolizumab was associated with a 17% improvement in the rate of pathological complete response (pCR) in the intention-to-treat population.
Among patients positive for PD-L1, atezolizumab was associated with a 20% improvement in pCR rate.
Patients have their say
At SABCS 2020, Dr. Mittendorf presented patient-reported outcomes (PRO) for 161 patients randomized to atezolizumab plus chemotherapy and 167 assigned to placebo plus chemotherapy.
The outcome measures – including role function (the ability to work or pursue common everyday activities), physical function, emotional and social function, and HRQOL – came from scores on the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30).
The exploratory PRO endpoints were mean function and disease- or treatment-related symptoms as well as mean change from baseline in these symptoms.
At baseline, mean physical function scores were high in both arms, at approximately 90%. They dropped to about 65% in each arm by cycle 5 and rebounded to about 80% by cycle 7.
“The change was clinically meaningful, in that the dip was greater than 10 points,” Dr. Mittendorf said. “As patients completed neoadjuvant therapy and were in the adjuvant phase of the study, there was an increase and stabilization with respect to their physical function.”
Similarly, role function declined from 89% in each arm at baseline to a nadir of about 55% in the placebo arm and 50% in the atezolizumab arm. After cycle 5, role function levels began to increase in both arms and remained above 70% from cycle 7 onward.
Role function did not completely recover or stabilize among patients in the atezolizumab arm, “and we attribute this to the fact that these patients continue to receive atezolizumab, which requires that they come to clinic for that therapy, thereby potentially impacting role function,” Dr. Mittendorf said.
She reported that HRQOL declined from a median of nearly 80% at baseline in both arms to a nadir of 62% in the placebo arm and 52% in the atezolizumab arm by cycle 5. HRQOL rebounded starting at cycle 6 and stabilized thereafter, with little daylight between the treatment arms at the most recent follow-up.
The investigators saw worsening of the treatment-related symptoms fatigue, nausea/vomiting, and diarrhea in each arm, with the highest level of symptoms except pain reported at cycle 5. The highest reported pain level was seen at cycle 4.
In each arm, the symptoms declined and stabilized in the adjuvant setting, with mean values at week 16 similar to those reported at baseline for most symptoms. The exception was fatigue, which remained slightly elevated in both arms.
Regarding side-effect bother, a similar proportion of patients in each arm reported increased level of bother by visit during the neoadjuvant phase. However, no additional side-effect bother was reported by patients receiving maintenance atezolizumab, compared with patients in the placebo arm, who were followed with observation alone.
‘Reassuring’ data
“What we can conclude from the PRO in IMpassion031 is that early breast cancer patients are relatively asymptomatic. They do have a good baseline quality of life and very good functioning. The neoadjuvant therapy certainly has deterioration in quality of life and functioning, but this is transient, and there was no evident burden from the atezolizumab,” said invited discussant Sylvia Adams, MD, of New York University.
She said it’s reassuring to see the addition of atezolizumab did not adversely affect HRQOL but added that the study “also shows that chemotherapy has a major impact on well-being, as expected.”
Questions and problems that still need to be addressed regarding the use of immunotherapies in early TNBC include whether every patient needs chemotherapy or immunotherapy, a lack of predictive biomarkers, whether increases in pCR rates after neoadjuvant immunotherapy and chemotherapy will translate into improved survival, and the optimal chemotherapy backbone and schedule, she said.
IMpassion031 is sponsored by F. Hoffman-LaRoche. Dr. Mittendorf disclosed relationships with Roche/Genentech, GlaxoSmithKline, Physicians’ Education Resource, AstraZeneca, Exact Sciences, Merck, Peregrine Pharmaceuticals, SELLAS Life Sciences, TapImmune, EMD Serono, Galena Biopharma, Bristol Myers Squibb, and Lilly. Dr. Adams disclosed relationships with Genentech, Bristol Myers Squibb, Merck, Amgen, Celgene, and Novartis.
SOURCE: Mittendorf E at al. SABCS 2020, Abstract GS3-02.
FROM SABCS 2020