Breast Cancer

SAN ANTONIO – Nice try, ATEMPT investigators, but trastuzumab emtansine (T-DM1) does not have a disease-free survival or safety advantage over paclitaxel plus trastuzumab in the adjuvant setting for patients with stage 1 HER2-positive breast cancer.

For 497 patients randomized on a 3:1 basis to receive either T-DM1 every 3 weeks for 17 cycles or paclitaxel plus trastuzumab (TH) weekly for 12 cycles followed by trastuzumab every 3 weeks for an additional 13 cycles, there were no significant between-regimen differences in the co-primary endpoints of 3-year disease-free survival (DFS) or clinically relevant toxicities, reported Sara M. Tolaney, MD, MPH of Dana-Farber Cancer Institute, Boston.

“While there was no difference in the overall incidence of clinically relevant toxicities between the two arms, there were differences in the toxicity profiles that were seen between T-DM1 and TH. It’s also important to know that not all toxicities that are significant for our patients are captured in this clinically relevant toxicity endpoint, such as alopecia, and patient-reported outcomes should be considered when assessing the tolerability of therapy,” she said at the San Antonio Breast Cancer Symposium.

For patients with stage 1, HER2-positive breast cancer at high risk of recurrence, paclitaxel and trastuzumab is associated with a 93% disease survival rate.

T-DM1, an drug antibody conjugate of trastuzumab and DM1, a cytotoxic agent, is active against metastatic HER2-positive breast cancer and in patients with residual disease after neoadjuvant HER2-directed therapy.

“Importantly, T-DM1 has been associated with less toxicity when compared to chemotherapy with trastuzumab,” said Dr. Tolaney.

To see whether T-DM1 could be a less toxic treatment option for patients with stage 1 HER2-positive breast cancer at risk for recurrence, the investigators enrolled 512 patients who were within 90 days of surgery, had N0 or microscopic N1 disease, left ventricular ejection fraction (LVEF) of 50% or greater, and no prior invasive breast cancer.

The patients were stratified by age (younger than 55 or 55 and older), planned radiation (yes or no), and planned hormonal therapy (yes or no), and then randomly assigned on a 3:1 basis to receive either T-DM1 3.6 mg/kg intravenously every 3 weeks for 17 cycles, or TH, consisting of paclitaxel 80 mg/m² plus trastuzumab 2 mg/kg intravenously weekly for 12 cycles, followed by trastuzumab 6 mg/kg every 3 weeks for an additional 13 cycles.

A total of 383 patients assigned to T-DM1 and 114 assigned to TH were included in the intention-to-treat analysis.

The study arms were well balanced by tumor size, histologic grade, hormone receptor status, and HER2 status by fluorescent in situ hybridization (1+, 2+, 3+ or not performed).

Three-year disease-free survival with was 97.7% with T-DM1 and 93.2% with TH, but the study was not powered to detect efficacy differences between the two adjuvant regimens, Dr. Tolaney noted.

In all, 46% of patients in each arm had clinically relevant toxicities. Grade 3 or greater nonhematologic toxicities were seen in 10% of those on T-DM1, vs. 11% of those on TH. Grade 2 or greater neurotoxicity was seen in 11% of patients and 23%, respectively.

Four patients on T-DM1 had grade 4 hematologic toxicity vs. none on TH. Febrile neutropenia was not seen among patients on T-DM1, but occurred in two patients on TH.

The incidence of toxicity requiring a dose delay was 28% and 26%, respectively, while nearly 3 times as many patients on T-DM1 had toxicities requiring early discontinuation (17% vs. 6%).

T-DM1 was also associated with higher incidences of grade 2 or greater thrombocytopenia (11% vs. 1%), alanine aminotransferase elevation (9% vs. 4%), and bilirubin increase (5% vs. 1%).

Three patients on T-DM1 and one on TH had symptomatic heart failure. Asymptomatic declines in LVEF were seen in five and seven patients, respectively.

“Given the low event rate seen in this trial, T-DM1 may be considered an alternative treatment approach to TH for select patients with stage 1 HER2-positive disease who are concerned about specific TH-related side effects and who understand the potential for T-DM1 toxicities. There may be some patients and physicians, however, who will want longer follow-up before adopting such an approach,” Dr. Tolaney said.

In the question and response session, an audience member said, “I would like to add one more toxicity that has not been considered, which is financial toxicity. There’s a huge difference in the price of both regimens, and the total cost of care.”

Dr. Tolaney replied that “certainly we did consider this and we had our pharmacist do some calculations looking at this financial toxicity, and it is true that a year of T-DM1 does cost a little more than two times as much as TH.”

She agreed that financial toxicity is a very important consideration when making treatment decisions, “but I think there are differences in toxicity profiles that do need to be considered when making individual decisions for our patients.”

Invited discussant A. Jo Chien, MD of the University of California, San Francisco noted that 75% of all patients enrolled in ATEMPT had hormone receptor positive disease “and therefore 3 years median follow-up is relatively short for this cohort.

“Due to the high rates of discontinuation in the T-DM1 arm, it is important to remember that duration of toxicity is a contributor to overall tolerability, which often is not well characterized by standard toxicity assessments, which often just report highest-grade toxicity at one point in time. High-grade toxicities that are short-lived may be acceptable, but low-grade toxicities for longer duration may not,” she said.

The ATEMPT trial was funded by Genentech. Dr. Tolaney has disclosed advisory board participation, institutional research funds, honoraria, and travel expense reimbursement from the company. Dr. Chien disclosed institutional research funding from Merck, Puma, Seattle Genetics, Astellas, and Amgen.

SOURCE: Tolaney SM et al. SABCS 2019, Abstract GS1-05.

SAN ANTONIO – Nice try, ATEMPT investigators, but trastuzumab emtansine (T-DM1) does not have a disease-free survival or safety advantage over paclitaxel plus trastuzumab in the adjuvant setting for patients with stage 1 HER2-positive breast cancer.

For 497 patients randomized on a 3:1 basis to receive either T-DM1 every 3 weeks for 17 cycles or paclitaxel plus trastuzumab (TH) weekly for 12 cycles followed by trastuzumab every 3 weeks for an additional 13 cycles, there were no significant between-regimen differences in the co-primary endpoints of 3-year disease-free survival (DFS) or clinically relevant toxicities, reported Sara M. Tolaney, MD, MPH of Dana-Farber Cancer Institute, Boston.

“While there was no difference in the overall incidence of clinically relevant toxicities between the two arms, there were differences in the toxicity profiles that were seen between T-DM1 and TH. It’s also important to know that not all toxicities that are significant for our patients are captured in this clinically relevant toxicity endpoint, such as alopecia, and patient-reported outcomes should be considered when assessing the tolerability of therapy,” she said at the San Antonio Breast Cancer Symposium.

For patients with stage 1, HER2-positive breast cancer at high risk of recurrence, paclitaxel and trastuzumab is associated with a 93% disease survival rate.

T-DM1, an drug antibody conjugate of trastuzumab and DM1, a cytotoxic agent, is active against metastatic HER2-positive breast cancer and in patients with residual disease after neoadjuvant HER2-directed therapy.

“Importantly, T-DM1 has been associated with less toxicity when compared to chemotherapy with trastuzumab,” said Dr. Tolaney.

To see whether T-DM1 could be a less toxic treatment option for patients with stage 1 HER2-positive breast cancer at risk for recurrence, the investigators enrolled 512 patients who were within 90 days of surgery, had N0 or microscopic N1 disease, left ventricular ejection fraction (LVEF) of 50% or greater, and no prior invasive breast cancer.

The patients were stratified by age (younger than 55 or 55 and older), planned radiation (yes or no), and planned hormonal therapy (yes or no), and then randomly assigned on a 3:1 basis to receive either T-DM1 3.6 mg/kg intravenously every 3 weeks for 17 cycles, or TH, consisting of paclitaxel 80 mg/m² plus trastuzumab 2 mg/kg intravenously weekly for 12 cycles, followed by trastuzumab 6 mg/kg every 3 weeks for an additional 13 cycles.

A total of 383 patients assigned to T-DM1 and 114 assigned to TH were included in the intention-to-treat analysis.

The study arms were well balanced by tumor size, histologic grade, hormone receptor status, and HER2 status by fluorescent in situ hybridization (1+, 2+, 3+ or not performed).

Three-year disease-free survival with was 97.7% with T-DM1 and 93.2% with TH, but the study was not powered to detect efficacy differences between the two adjuvant regimens, Dr. Tolaney noted.

In all, 46% of patients in each arm had clinically relevant toxicities. Grade 3 or greater nonhematologic toxicities were seen in 10% of those on T-DM1, vs. 11% of those on TH. Grade 2 or greater neurotoxicity was seen in 11% of patients and 23%, respectively.

Four patients on T-DM1 had grade 4 hematologic toxicity vs. none on TH. Febrile neutropenia was not seen among patients on T-DM1, but occurred in two patients on TH.

The incidence of toxicity requiring a dose delay was 28% and 26%, respectively, while nearly 3 times as many patients on T-DM1 had toxicities requiring early discontinuation (17% vs. 6%).

T-DM1 was also associated with higher incidences of grade 2 or greater thrombocytopenia (11% vs. 1%), alanine aminotransferase elevation (9% vs. 4%), and bilirubin increase (5% vs. 1%).

Three patients on T-DM1 and one on TH had symptomatic heart failure. Asymptomatic declines in LVEF were seen in five and seven patients, respectively.

“Given the low event rate seen in this trial, T-DM1 may be considered an alternative treatment approach to TH for select patients with stage 1 HER2-positive disease who are concerned about specific TH-related side effects and who understand the potential for T-DM1 toxicities. There may be some patients and physicians, however, who will want longer follow-up before adopting such an approach,” Dr. Tolaney said.

In the question and response session, an audience member said, “I would like to add one more toxicity that has not been considered, which is financial toxicity. There’s a huge difference in the price of both regimens, and the total cost of care.”

Dr. Tolaney replied that “certainly we did consider this and we had our pharmacist do some calculations looking at this financial toxicity, and it is true that a year of T-DM1 does cost a little more than two times as much as TH.”

She agreed that financial toxicity is a very important consideration when making treatment decisions, “but I think there are differences in toxicity profiles that do need to be considered when making individual decisions for our patients.”

Invited discussant A. Jo Chien, MD of the University of California, San Francisco noted that 75% of all patients enrolled in ATEMPT had hormone receptor positive disease “and therefore 3 years median follow-up is relatively short for this cohort.

“Due to the high rates of discontinuation in the T-DM1 arm, it is important to remember that duration of toxicity is a contributor to overall tolerability, which often is not well characterized by standard toxicity assessments, which often just report highest-grade toxicity at one point in time. High-grade toxicities that are short-lived may be acceptable, but low-grade toxicities for longer duration may not,” she said.

The ATEMPT trial was funded by Genentech. Dr. Tolaney has disclosed advisory board participation, institutional research funds, honoraria, and travel expense reimbursement from the company. Dr. Chien disclosed institutional research funding from Merck, Puma, Seattle Genetics, Astellas, and Amgen.

SOURCE: Tolaney SM et al. SABCS 2019, Abstract GS1-05.

SAN ANTONIO – Nice try, ATEMPT investigators, but trastuzumab emtansine (T-DM1) does not have a disease-free survival or safety advantage over paclitaxel plus trastuzumab in the adjuvant setting for patients with stage 1 HER2-positive breast cancer.

For 497 patients randomized on a 3:1 basis to receive either T-DM1 every 3 weeks for 17 cycles or paclitaxel plus trastuzumab (TH) weekly for 12 cycles followed by trastuzumab every 3 weeks for an additional 13 cycles, there were no significant between-regimen differences in the co-primary endpoints of 3-year disease-free survival (DFS) or clinically relevant toxicities, reported Sara M. Tolaney, MD, MPH of Dana-Farber Cancer Institute, Boston.

“While there was no difference in the overall incidence of clinically relevant toxicities between the two arms, there were differences in the toxicity profiles that were seen between T-DM1 and TH. It’s also important to know that not all toxicities that are significant for our patients are captured in this clinically relevant toxicity endpoint, such as alopecia, and patient-reported outcomes should be considered when assessing the tolerability of therapy,” she said at the San Antonio Breast Cancer Symposium.

For patients with stage 1, HER2-positive breast cancer at high risk of recurrence, paclitaxel and trastuzumab is associated with a 93% disease survival rate.

T-DM1, an drug antibody conjugate of trastuzumab and DM1, a cytotoxic agent, is active against metastatic HER2-positive breast cancer and in patients with residual disease after neoadjuvant HER2-directed therapy.

“Importantly, T-DM1 has been associated with less toxicity when compared to chemotherapy with trastuzumab,” said Dr. Tolaney.

To see whether T-DM1 could be a less toxic treatment option for patients with stage 1 HER2-positive breast cancer at risk for recurrence, the investigators enrolled 512 patients who were within 90 days of surgery, had N0 or microscopic N1 disease, left ventricular ejection fraction (LVEF) of 50% or greater, and no prior invasive breast cancer.

The patients were stratified by age (younger than 55 or 55 and older), planned radiation (yes or no), and planned hormonal therapy (yes or no), and then randomly assigned on a 3:1 basis to receive either T-DM1 3.6 mg/kg intravenously every 3 weeks for 17 cycles, or TH, consisting of paclitaxel 80 mg/m² plus trastuzumab 2 mg/kg intravenously weekly for 12 cycles, followed by trastuzumab 6 mg/kg every 3 weeks for an additional 13 cycles.

A total of 383 patients assigned to T-DM1 and 114 assigned to TH were included in the intention-to-treat analysis.

The study arms were well balanced by tumor size, histologic grade, hormone receptor status, and HER2 status by fluorescent in situ hybridization (1+, 2+, 3+ or not performed).

Three-year disease-free survival with was 97.7% with T-DM1 and 93.2% with TH, but the study was not powered to detect efficacy differences between the two adjuvant regimens, Dr. Tolaney noted.

In all, 46% of patients in each arm had clinically relevant toxicities. Grade 3 or greater nonhematologic toxicities were seen in 10% of those on T-DM1, vs. 11% of those on TH. Grade 2 or greater neurotoxicity was seen in 11% of patients and 23%, respectively.

Four patients on T-DM1 had grade 4 hematologic toxicity vs. none on TH. Febrile neutropenia was not seen among patients on T-DM1, but occurred in two patients on TH.

The incidence of toxicity requiring a dose delay was 28% and 26%, respectively, while nearly 3 times as many patients on T-DM1 had toxicities requiring early discontinuation (17% vs. 6%).

T-DM1 was also associated with higher incidences of grade 2 or greater thrombocytopenia (11% vs. 1%), alanine aminotransferase elevation (9% vs. 4%), and bilirubin increase (5% vs. 1%).

Three patients on T-DM1 and one on TH had symptomatic heart failure. Asymptomatic declines in LVEF were seen in five and seven patients, respectively.

“Given the low event rate seen in this trial, T-DM1 may be considered an alternative treatment approach to TH for select patients with stage 1 HER2-positive disease who are concerned about specific TH-related side effects and who understand the potential for T-DM1 toxicities. There may be some patients and physicians, however, who will want longer follow-up before adopting such an approach,” Dr. Tolaney said.

In the question and response session, an audience member said, “I would like to add one more toxicity that has not been considered, which is financial toxicity. There’s a huge difference in the price of both regimens, and the total cost of care.”

Dr. Tolaney replied that “certainly we did consider this and we had our pharmacist do some calculations looking at this financial toxicity, and it is true that a year of T-DM1 does cost a little more than two times as much as TH.”

She agreed that financial toxicity is a very important consideration when making treatment decisions, “but I think there are differences in toxicity profiles that do need to be considered when making individual decisions for our patients.”

Invited discussant A. Jo Chien, MD of the University of California, San Francisco noted that 75% of all patients enrolled in ATEMPT had hormone receptor positive disease “and therefore 3 years median follow-up is relatively short for this cohort.

“Due to the high rates of discontinuation in the T-DM1 arm, it is important to remember that duration of toxicity is a contributor to overall tolerability, which often is not well characterized by standard toxicity assessments, which often just report highest-grade toxicity at one point in time. High-grade toxicities that are short-lived may be acceptable, but low-grade toxicities for longer duration may not,” she said.

The ATEMPT trial was funded by Genentech. Dr. Tolaney has disclosed advisory board participation, institutional research funds, honoraria, and travel expense reimbursement from the company. Dr. Chien disclosed institutional research funding from Merck, Puma, Seattle Genetics, Astellas, and Amgen.

SOURCE: Tolaney SM et al. SABCS 2019, Abstract GS1-05.

Adjuvant denosumab did not improve bone metastasis–free survival and related outcomes in women with early-stage breast cancer, according to a phase 3 trial.

“We hypothesised that denosumab would modify the clinical course of early breast cancer, delaying the development of clinical bone metastases with or without disease recurrence at other sites,” reported Robert Coleman, MBBS, MD, of the University of Sheffield, England, and colleagues. Their report is in The Lancet Oncology.

The randomized, placebo-controlled, phase 3 D-CARE study included 4,509 women with early-stage, high-risk disease. The effects of adding denosumab to standard-of-care adjuvant or neoadjuvant chemotherapy was studied in 389 institutions around the globe. In the initial treatment phase, study patients received denosumab or placebo every 3-4 weeks in combination with adjuvant or neoadjuvant chemotherapy for approximately 6 months.

After completion of chemotherapy, the dosing interval was extended to every 12 weeks (range, 14 days) for a total of 5 years. The median age of women who received denosumab was 50 years (range, 44-59 years), 65% of whom were hormone receptor positive, HER2-negative. In the study, patients were stratified by various factors, including type of therapy, age, lymph node status, geographical region, and others. The primary outcome was a composite endpoint of bone metastasis–free survival.

At 5-year follow-up, the researchers found no significant difference in bone metastasis–free survival between the denosumab and placebo treatment arms (median survival not reached in either arm; P = .70). With respect to safety, the most frequently seen grade 3 or higher treatment-emergent adverse events were neutropenia (15% vs. 15%), febrile neutropenia (5% vs. 6%), and leukopenia (3% vs. 3%). Positively adjudicated osteonecrosis of the jaw occurred in 122 (5%) of 2,241 patients treated with denosumab versus 4 (less than 1%) of 2,218 patients treated with placebo, Dr. Coleman and colleagues wrote.

The researchers acknowledged that a key limitation of the study was the smaller than anticipated number of events for efficacy outcomes. As a result, the study protocol was modified, which could have limited the statistical power of the study. “The results of this study do not support a role for denosumab as an antitumour agent in this setting,” they concluded.

Amgen funded the study. The authors reported financial affiliations with AbbVie, Amgen, Astellas, Bristol-Myers Squibb, Celgene, Covance, Lilly, Medivation, Merck Serono, Merck Sharp and Dohme, Novartis, Pfizer, and several others.

SOURCE: Coleman R et al. Lancet Oncol. 2019 Dec 2. doi: 10.1016/S1470-2045(19)30687-4.

Adjuvant denosumab did not improve bone metastasis–free survival and related outcomes in women with early-stage breast cancer, according to a phase 3 trial.

“We hypothesised that denosumab would modify the clinical course of early breast cancer, delaying the development of clinical bone metastases with or without disease recurrence at other sites,” reported Robert Coleman, MBBS, MD, of the University of Sheffield, England, and colleagues. Their report is in The Lancet Oncology.

The randomized, placebo-controlled, phase 3 D-CARE study included 4,509 women with early-stage, high-risk disease. The effects of adding denosumab to standard-of-care adjuvant or neoadjuvant chemotherapy was studied in 389 institutions around the globe. In the initial treatment phase, study patients received denosumab or placebo every 3-4 weeks in combination with adjuvant or neoadjuvant chemotherapy for approximately 6 months.

After completion of chemotherapy, the dosing interval was extended to every 12 weeks (range, 14 days) for a total of 5 years. The median age of women who received denosumab was 50 years (range, 44-59 years), 65% of whom were hormone receptor positive, HER2-negative. In the study, patients were stratified by various factors, including type of therapy, age, lymph node status, geographical region, and others. The primary outcome was a composite endpoint of bone metastasis–free survival.

At 5-year follow-up, the researchers found no significant difference in bone metastasis–free survival between the denosumab and placebo treatment arms (median survival not reached in either arm; P = .70). With respect to safety, the most frequently seen grade 3 or higher treatment-emergent adverse events were neutropenia (15% vs. 15%), febrile neutropenia (5% vs. 6%), and leukopenia (3% vs. 3%). Positively adjudicated osteonecrosis of the jaw occurred in 122 (5%) of 2,241 patients treated with denosumab versus 4 (less than 1%) of 2,218 patients treated with placebo, Dr. Coleman and colleagues wrote.

The researchers acknowledged that a key limitation of the study was the smaller than anticipated number of events for efficacy outcomes. As a result, the study protocol was modified, which could have limited the statistical power of the study. “The results of this study do not support a role for denosumab as an antitumour agent in this setting,” they concluded.

Amgen funded the study. The authors reported financial affiliations with AbbVie, Amgen, Astellas, Bristol-Myers Squibb, Celgene, Covance, Lilly, Medivation, Merck Serono, Merck Sharp and Dohme, Novartis, Pfizer, and several others.

SOURCE: Coleman R et al. Lancet Oncol. 2019 Dec 2. doi: 10.1016/S1470-2045(19)30687-4.

Adjuvant denosumab did not improve bone metastasis–free survival and related outcomes in women with early-stage breast cancer, according to a phase 3 trial.

“We hypothesised that denosumab would modify the clinical course of early breast cancer, delaying the development of clinical bone metastases with or without disease recurrence at other sites,” reported Robert Coleman, MBBS, MD, of the University of Sheffield, England, and colleagues. Their report is in The Lancet Oncology.

The randomized, placebo-controlled, phase 3 D-CARE study included 4,509 women with early-stage, high-risk disease. The effects of adding denosumab to standard-of-care adjuvant or neoadjuvant chemotherapy was studied in 389 institutions around the globe. In the initial treatment phase, study patients received denosumab or placebo every 3-4 weeks in combination with adjuvant or neoadjuvant chemotherapy for approximately 6 months.

After completion of chemotherapy, the dosing interval was extended to every 12 weeks (range, 14 days) for a total of 5 years. The median age of women who received denosumab was 50 years (range, 44-59 years), 65% of whom were hormone receptor positive, HER2-negative. In the study, patients were stratified by various factors, including type of therapy, age, lymph node status, geographical region, and others. The primary outcome was a composite endpoint of bone metastasis–free survival.

At 5-year follow-up, the researchers found no significant difference in bone metastasis–free survival between the denosumab and placebo treatment arms (median survival not reached in either arm; P = .70). With respect to safety, the most frequently seen grade 3 or higher treatment-emergent adverse events were neutropenia (15% vs. 15%), febrile neutropenia (5% vs. 6%), and leukopenia (3% vs. 3%). Positively adjudicated osteonecrosis of the jaw occurred in 122 (5%) of 2,241 patients treated with denosumab versus 4 (less than 1%) of 2,218 patients treated with placebo, Dr. Coleman and colleagues wrote.

The researchers acknowledged that a key limitation of the study was the smaller than anticipated number of events for efficacy outcomes. As a result, the study protocol was modified, which could have limited the statistical power of the study. “The results of this study do not support a role for denosumab as an antitumour agent in this setting,” they concluded.

Amgen funded the study. The authors reported financial affiliations with AbbVie, Amgen, Astellas, Bristol-Myers Squibb, Celgene, Covance, Lilly, Medivation, Merck Serono, Merck Sharp and Dohme, Novartis, Pfizer, and several others.

SOURCE: Coleman R et al. Lancet Oncol. 2019 Dec 2. doi: 10.1016/S1470-2045(19)30687-4.

Bilateral mastectomy significantly decreases the risk for a second contralateral breast cancer, but does not decrease the risk of death, compared with breast-conserving therapy, results of a large retrospective study indicate.

Among 245,418 patients followed for a median of 6.7 years, the risk of death from breast cancer was similar for those who had undergone either breast-conserving therapy or bilateral mastectomy (BLM) but was 20% higher among women who had undergone unilateral mastectomy (ULM) when compared with breast-conserving therapy, reported Allison W. Kurian, MD, MSc, from Stanford (Calif.) University, and colleagues.

“Second breast cancers are rare, and their reduction should be weighed against the harms associated with BLM,” they wrote in a study published online in Cancer.

The investigators extracted data from the Surveillance, Epidemiology, and End Results program on all women diagnosed with American Joint Committee on Cancer stage 0 to stage III unilateral breast cancer in California from 1998 to 2015 who were treated with either BLM versus breast-conserving therapy, including surgery and radiation or unilateral mastectomy.­­

They calculated the absolute excess risk of contralateral breast cancer as the observed minus expected number of breast cancers in the general population divided by 10,000 person-years at risk.

­Of 421,643 women with a first diagnosis of primary breast cancer during the study period, 245,418 met the study criteria. Of this cohort, 7,784 (3.2%) developed a contralateral second breast cancer more than 6 months after diagnosis of the first, after a median 6.7 years of follow-up.

Slightly more than half of the cohort (52.1%) had undergone breast-conserving therapy, 37.5% underwent unilateral mastectomy, and 7.6% had bilateral mastectomy. An additional 2.9% of patients were women aged 70 years and older with stage I hormone receptor–positive, HER2-negative disease who underwent breast-conserving surgery without radiation (percentages exceed 100% because of rounding).

A multivariate-adjusted model showed that, as might be expected, patients who underwent bilateral mastectomy had a 90% reduction in risk of contralateral cancer (hazard ratio, 0.10; P less than .001), compared with breast-conserving therapy. In contrast, patients who underwent unilateral mastectomy had a slight but significant increase in risk for a second contralateral breast cancer (HR, 1.07; P = .008).

The absolute excess risk for second contralateral breast cancer was 5 per 10,000 person-years with breast-conserving therapy, 13.6 per 10,000 person-years with unilateral mastectomy, and –28.6 per 10,000 person-years with bilateral mastectomy.

When they looked at risk for death, however they found that, compared with breast-conserving therapy, breast-conserving surgery alone (HR, 1.36; P = .0001) and unilateral mastectomy (HR, 1.21; P less than .001), but not bilateral mastectomy (HR, 1.03; P = .35) were significantly associated with increased risk for breast cancer death.

The authors noted that their estimates of absolute risk of second contralateral breast cancer jibe with those of earlier studies, and can help clinicians frame the discussion of the benefits versus risks for individual patients.

“What one patient might consider to be a negligible benefit of BLM, weighed against its potential harms of greater pain, recovery time, and impact on body image and employment, might appear worthwhile to another,” they wrote.

The study was funded by the National Cancer Institute, National Institutes of Health, Department of Health & Human Services, Suzanne Pride Bryan Fund for Breast Cancer Research, Jan Weimer Faculty Chair for Breast Oncology, and the BRCA Foundation. Dr. Kurian disclosed institutional research funding from Myriad Genetics.

SOURCE: Kurin AW et al. Cancer. 2019 Nov 21. doi: 10.1002/cncr.32618.

Bilateral mastectomy significantly decreases the risk for a second contralateral breast cancer, but does not decrease the risk of death, compared with breast-conserving therapy, results of a large retrospective study indicate.

Among 245,418 patients followed for a median of 6.7 years, the risk of death from breast cancer was similar for those who had undergone either breast-conserving therapy or bilateral mastectomy (BLM) but was 20% higher among women who had undergone unilateral mastectomy (ULM) when compared with breast-conserving therapy, reported Allison W. Kurian, MD, MSc, from Stanford (Calif.) University, and colleagues.

“Second breast cancers are rare, and their reduction should be weighed against the harms associated with BLM,” they wrote in a study published online in Cancer.

The investigators extracted data from the Surveillance, Epidemiology, and End Results program on all women diagnosed with American Joint Committee on Cancer stage 0 to stage III unilateral breast cancer in California from 1998 to 2015 who were treated with either BLM versus breast-conserving therapy, including surgery and radiation or unilateral mastectomy.­­

They calculated the absolute excess risk of contralateral breast cancer as the observed minus expected number of breast cancers in the general population divided by 10,000 person-years at risk.

­Of 421,643 women with a first diagnosis of primary breast cancer during the study period, 245,418 met the study criteria. Of this cohort, 7,784 (3.2%) developed a contralateral second breast cancer more than 6 months after diagnosis of the first, after a median 6.7 years of follow-up.

Slightly more than half of the cohort (52.1%) had undergone breast-conserving therapy, 37.5% underwent unilateral mastectomy, and 7.6% had bilateral mastectomy. An additional 2.9% of patients were women aged 70 years and older with stage I hormone receptor–positive, HER2-negative disease who underwent breast-conserving surgery without radiation (percentages exceed 100% because of rounding).

A multivariate-adjusted model showed that, as might be expected, patients who underwent bilateral mastectomy had a 90% reduction in risk of contralateral cancer (hazard ratio, 0.10; P less than .001), compared with breast-conserving therapy. In contrast, patients who underwent unilateral mastectomy had a slight but significant increase in risk for a second contralateral breast cancer (HR, 1.07; P = .008).

The absolute excess risk for second contralateral breast cancer was 5 per 10,000 person-years with breast-conserving therapy, 13.6 per 10,000 person-years with unilateral mastectomy, and –28.6 per 10,000 person-years with bilateral mastectomy.

When they looked at risk for death, however they found that, compared with breast-conserving therapy, breast-conserving surgery alone (HR, 1.36; P = .0001) and unilateral mastectomy (HR, 1.21; P less than .001), but not bilateral mastectomy (HR, 1.03; P = .35) were significantly associated with increased risk for breast cancer death.

The authors noted that their estimates of absolute risk of second contralateral breast cancer jibe with those of earlier studies, and can help clinicians frame the discussion of the benefits versus risks for individual patients.

“What one patient might consider to be a negligible benefit of BLM, weighed against its potential harms of greater pain, recovery time, and impact on body image and employment, might appear worthwhile to another,” they wrote.

The study was funded by the National Cancer Institute, National Institutes of Health, Department of Health & Human Services, Suzanne Pride Bryan Fund for Breast Cancer Research, Jan Weimer Faculty Chair for Breast Oncology, and the BRCA Foundation. Dr. Kurian disclosed institutional research funding from Myriad Genetics.

SOURCE: Kurin AW et al. Cancer. 2019 Nov 21. doi: 10.1002/cncr.32618.

Bilateral mastectomy significantly decreases the risk for a second contralateral breast cancer, but does not decrease the risk of death, compared with breast-conserving therapy, results of a large retrospective study indicate.

Among 245,418 patients followed for a median of 6.7 years, the risk of death from breast cancer was similar for those who had undergone either breast-conserving therapy or bilateral mastectomy (BLM) but was 20% higher among women who had undergone unilateral mastectomy (ULM) when compared with breast-conserving therapy, reported Allison W. Kurian, MD, MSc, from Stanford (Calif.) University, and colleagues.

“Second breast cancers are rare, and their reduction should be weighed against the harms associated with BLM,” they wrote in a study published online in Cancer.

The investigators extracted data from the Surveillance, Epidemiology, and End Results program on all women diagnosed with American Joint Committee on Cancer stage 0 to stage III unilateral breast cancer in California from 1998 to 2015 who were treated with either BLM versus breast-conserving therapy, including surgery and radiation or unilateral mastectomy.­­

They calculated the absolute excess risk of contralateral breast cancer as the observed minus expected number of breast cancers in the general population divided by 10,000 person-years at risk.

­Of 421,643 women with a first diagnosis of primary breast cancer during the study period, 245,418 met the study criteria. Of this cohort, 7,784 (3.2%) developed a contralateral second breast cancer more than 6 months after diagnosis of the first, after a median 6.7 years of follow-up.

Slightly more than half of the cohort (52.1%) had undergone breast-conserving therapy, 37.5% underwent unilateral mastectomy, and 7.6% had bilateral mastectomy. An additional 2.9% of patients were women aged 70 years and older with stage I hormone receptor–positive, HER2-negative disease who underwent breast-conserving surgery without radiation (percentages exceed 100% because of rounding).

A multivariate-adjusted model showed that, as might be expected, patients who underwent bilateral mastectomy had a 90% reduction in risk of contralateral cancer (hazard ratio, 0.10; P less than .001), compared with breast-conserving therapy. In contrast, patients who underwent unilateral mastectomy had a slight but significant increase in risk for a second contralateral breast cancer (HR, 1.07; P = .008).

The absolute excess risk for second contralateral breast cancer was 5 per 10,000 person-years with breast-conserving therapy, 13.6 per 10,000 person-years with unilateral mastectomy, and –28.6 per 10,000 person-years with bilateral mastectomy.

When they looked at risk for death, however they found that, compared with breast-conserving therapy, breast-conserving surgery alone (HR, 1.36; P = .0001) and unilateral mastectomy (HR, 1.21; P less than .001), but not bilateral mastectomy (HR, 1.03; P = .35) were significantly associated with increased risk for breast cancer death.

The authors noted that their estimates of absolute risk of second contralateral breast cancer jibe with those of earlier studies, and can help clinicians frame the discussion of the benefits versus risks for individual patients.

“What one patient might consider to be a negligible benefit of BLM, weighed against its potential harms of greater pain, recovery time, and impact on body image and employment, might appear worthwhile to another,” they wrote.

The study was funded by the National Cancer Institute, National Institutes of Health, Department of Health & Human Services, Suzanne Pride Bryan Fund for Breast Cancer Research, Jan Weimer Faculty Chair for Breast Oncology, and the BRCA Foundation. Dr. Kurian disclosed institutional research funding from Myriad Genetics.

SOURCE: Kurin AW et al. Cancer. 2019 Nov 21. doi: 10.1002/cncr.32618.

The introduction over the last decade of new systemic therapies for the treatment of hormone receptor positive, HER2-negative metastatic breast cancer has not translated into improved survival in a real-world setting, results of a retrospective study suggest.

Among 2,197 patients who received at least one line of systemic therapy for hormone receptor positive, HER2-negative metastatic breast cancer (HR+/HER2– MBC) from 2003 to 2013, there were no significant differences in median duration of hormonal therapy or median overall survival (OS) for patients treated in any of three time spans during that 10-year period, reported Dan Le, MD, MHA, of BC Cancer, Surrey, B.C., and colleagues.

“Despite the introduction of 9 new adjuvant therapies and 2 new metastatic treatments, survival in the metastatic setting for HR-positive, HER2-negative breast cancer did not improve between 2003 and 2013,” they wrote in a report published in Cancer.

Improvements in adjuvant therapy such as the introduction of cyclin-dependent kinase inhibitors (CDKI) may result in fewer relapses but may also affect the response of relapsed cancers to additional lines of therapy, the authors contended.

“Improved adjuvant therapy means that the cancers that do relapse may have more adverse biology, either intrinsically or because of selective pressure and clonal evolution from exposure to more and better drugs in the adjuvant setting. These factors could, in part, explain the lack of improved survival over time observed in this study,” they wrote.

To see whether significant increases in progression-free survival (PFS) in a clinical trial translated into improved outcomes – including OS – in population-based settings, the investigators identified 2,432 patients with HR+/HER2– MBC from data in the prospective Breast Cancer Outcomes Unit Database of BC Cancer. Of this group, 2,197 received at least one line of systemic therapy after an MBC diagnosis, and 1,752 received first and/or second-line hormonal therapy as well.

The patients were treated in one of three time cohorts: from 2003 through 2005, 2007 through 2009, or 2011 through 2013.

Nine new adjuvant systemic therapies with or without neoadjuvant therapy were approved by BC Cancer during the study period. For the entire decade of the study, the mean survival time was 3.1 years, and the median OS was 2.0 years.

The longest survival for patients diagnosed from 2003 through 2005 was 14.6 years, with 18.1% of these patients living at least 5 years after diagnosis. For patients diagnosed from 2007 through 2009, the longest survival was 10.6 years, with 17.7% of these patients living 5 years or longer post diagnosis. For patients in the most recent cohort (with patients diagnosed after August 2012 excluded), the longest survival was 6.6 years, with 17.3% living at least 5 years after diagnosis.

Overall, patients had a median of 9 months of first-line hormonal treatment, and 6.1 months of second-line hormonal therapy, with nearly identical duration across all three time cohorts.

“Ultimately, it seems likely that the greater the proportion of patients we cure with modern adjuvant therapy, the more challenging it will be to improve outcomes for patients with relapsed disease. This underscores the importance of 1) making continued progress in the adjuvant management of potentially curable breast cancer by first studying new therapeutic agents in the metastatic setting and 2) developing a better understanding of how selective pressure and clonal evolution may lead to more resistant biologic phenotypes in MBC,” the investigators wrote.

No specific study funding was disclosed. No authors disclosed potential conflicts of interest.

SOURCE: Le D et al. Cancer 2019 Nov 21. doi: 10.1002/cncr.32631.

The introduction over the last decade of new systemic therapies for the treatment of hormone receptor positive, HER2-negative metastatic breast cancer has not translated into improved survival in a real-world setting, results of a retrospective study suggest.

Among 2,197 patients who received at least one line of systemic therapy for hormone receptor positive, HER2-negative metastatic breast cancer (HR+/HER2– MBC) from 2003 to 2013, there were no significant differences in median duration of hormonal therapy or median overall survival (OS) for patients treated in any of three time spans during that 10-year period, reported Dan Le, MD, MHA, of BC Cancer, Surrey, B.C., and colleagues.

“Despite the introduction of 9 new adjuvant therapies and 2 new metastatic treatments, survival in the metastatic setting for HR-positive, HER2-negative breast cancer did not improve between 2003 and 2013,” they wrote in a report published in Cancer.

Improvements in adjuvant therapy such as the introduction of cyclin-dependent kinase inhibitors (CDKI) may result in fewer relapses but may also affect the response of relapsed cancers to additional lines of therapy, the authors contended.

“Improved adjuvant therapy means that the cancers that do relapse may have more adverse biology, either intrinsically or because of selective pressure and clonal evolution from exposure to more and better drugs in the adjuvant setting. These factors could, in part, explain the lack of improved survival over time observed in this study,” they wrote.

To see whether significant increases in progression-free survival (PFS) in a clinical trial translated into improved outcomes – including OS – in population-based settings, the investigators identified 2,432 patients with HR+/HER2– MBC from data in the prospective Breast Cancer Outcomes Unit Database of BC Cancer. Of this group, 2,197 received at least one line of systemic therapy after an MBC diagnosis, and 1,752 received first and/or second-line hormonal therapy as well.

The patients were treated in one of three time cohorts: from 2003 through 2005, 2007 through 2009, or 2011 through 2013.

Nine new adjuvant systemic therapies with or without neoadjuvant therapy were approved by BC Cancer during the study period. For the entire decade of the study, the mean survival time was 3.1 years, and the median OS was 2.0 years.

The longest survival for patients diagnosed from 2003 through 2005 was 14.6 years, with 18.1% of these patients living at least 5 years after diagnosis. For patients diagnosed from 2007 through 2009, the longest survival was 10.6 years, with 17.7% of these patients living 5 years or longer post diagnosis. For patients in the most recent cohort (with patients diagnosed after August 2012 excluded), the longest survival was 6.6 years, with 17.3% living at least 5 years after diagnosis.

Overall, patients had a median of 9 months of first-line hormonal treatment, and 6.1 months of second-line hormonal therapy, with nearly identical duration across all three time cohorts.

“Ultimately, it seems likely that the greater the proportion of patients we cure with modern adjuvant therapy, the more challenging it will be to improve outcomes for patients with relapsed disease. This underscores the importance of 1) making continued progress in the adjuvant management of potentially curable breast cancer by first studying new therapeutic agents in the metastatic setting and 2) developing a better understanding of how selective pressure and clonal evolution may lead to more resistant biologic phenotypes in MBC,” the investigators wrote.

No specific study funding was disclosed. No authors disclosed potential conflicts of interest.

SOURCE: Le D et al. Cancer 2019 Nov 21. doi: 10.1002/cncr.32631.

The introduction over the last decade of new systemic therapies for the treatment of hormone receptor positive, HER2-negative metastatic breast cancer has not translated into improved survival in a real-world setting, results of a retrospective study suggest.

Among 2,197 patients who received at least one line of systemic therapy for hormone receptor positive, HER2-negative metastatic breast cancer (HR+/HER2– MBC) from 2003 to 2013, there were no significant differences in median duration of hormonal therapy or median overall survival (OS) for patients treated in any of three time spans during that 10-year period, reported Dan Le, MD, MHA, of BC Cancer, Surrey, B.C., and colleagues.

“Despite the introduction of 9 new adjuvant therapies and 2 new metastatic treatments, survival in the metastatic setting for HR-positive, HER2-negative breast cancer did not improve between 2003 and 2013,” they wrote in a report published in Cancer.

Improvements in adjuvant therapy such as the introduction of cyclin-dependent kinase inhibitors (CDKI) may result in fewer relapses but may also affect the response of relapsed cancers to additional lines of therapy, the authors contended.

“Improved adjuvant therapy means that the cancers that do relapse may have more adverse biology, either intrinsically or because of selective pressure and clonal evolution from exposure to more and better drugs in the adjuvant setting. These factors could, in part, explain the lack of improved survival over time observed in this study,” they wrote.

To see whether significant increases in progression-free survival (PFS) in a clinical trial translated into improved outcomes – including OS – in population-based settings, the investigators identified 2,432 patients with HR+/HER2– MBC from data in the prospective Breast Cancer Outcomes Unit Database of BC Cancer. Of this group, 2,197 received at least one line of systemic therapy after an MBC diagnosis, and 1,752 received first and/or second-line hormonal therapy as well.

The patients were treated in one of three time cohorts: from 2003 through 2005, 2007 through 2009, or 2011 through 2013.

Nine new adjuvant systemic therapies with or without neoadjuvant therapy were approved by BC Cancer during the study period. For the entire decade of the study, the mean survival time was 3.1 years, and the median OS was 2.0 years.

The longest survival for patients diagnosed from 2003 through 2005 was 14.6 years, with 18.1% of these patients living at least 5 years after diagnosis. For patients diagnosed from 2007 through 2009, the longest survival was 10.6 years, with 17.7% of these patients living 5 years or longer post diagnosis. For patients in the most recent cohort (with patients diagnosed after August 2012 excluded), the longest survival was 6.6 years, with 17.3% living at least 5 years after diagnosis.

Overall, patients had a median of 9 months of first-line hormonal treatment, and 6.1 months of second-line hormonal therapy, with nearly identical duration across all three time cohorts.

“Ultimately, it seems likely that the greater the proportion of patients we cure with modern adjuvant therapy, the more challenging it will be to improve outcomes for patients with relapsed disease. This underscores the importance of 1) making continued progress in the adjuvant management of potentially curable breast cancer by first studying new therapeutic agents in the metastatic setting and 2) developing a better understanding of how selective pressure and clonal evolution may lead to more resistant biologic phenotypes in MBC,” the investigators wrote.

No specific study funding was disclosed. No authors disclosed potential conflicts of interest.

SOURCE: Le D et al. Cancer 2019 Nov 21. doi: 10.1002/cncr.32631.

Single-fraction radiation could not be shown to be noninferior to multi-fraction radiation at improving walking function in patients with spinal compression from metastatic cancer, but the small differences seen in a noninferiority trial may not matter to patients, investigators suggest.

Among 686 patients with spinal compression from metastatic cancer randomly assigned in a clinical trial to receive either 8 Gy of radiation in a single fraction or 20 Gy delivered in 5 fractions over 5 consecutive days, 69.3% of patients in the single-fraction arm had good ambulatory status at 8 weeks, compared with 72.7% of patients in the multi-fraction arm (P for noninferiority = .06), reported Peter J Hoskin, BSc, MBBS, MD, of Mount Vernon Cancer Centre in Northwood, England, and colleagues.

The trial did not meet the endpoint of noninferiority of single-fraction radiation for improving ambulation at 8 weeks because the lower limit of the 95% confidence interval (CI) was –11.5%, overlapping the noninferiority margin of –11%.

“However, for all other time points, the CI limits were within the noninferiority margin, and the observed risk differences between single-fraction and multi-fraction radiotherapy groups in ambulatory status were small and unlikely to be of clinical importance,” the investigators wrote in JAMA.

The authors note that although radiotherapy is widely used as a palliative measure for patients with spinal canal compression caused my metastatic disease, there is no agreement on the optimum schedule, with some guidelines recommending higher doses in multiple fractions, and others recommending a single 8 Gy does for patients with painful spinal sites.

To see whether single-fraction radiation could be noninferior to multi-fraction, the investigators enrolled patients in 42 sites in the United Kingdom and 5 in Australia into the SCORAD trial, and randomly assigned them to either single-fraction (345 patients) or multi-fraction (341 patients) radiation. The median age of those enrolled was 70 years, and 44% had prostate cancer, 19% had lung cancer, and 12% had breast cancer.

As noted, the primary endpoint of noninferiority of single-fraction radiation at improving ambulatory status at week 8 was not met. Ambulatory status was based on a 4-point scale and was classified as either grade 1: ambulatory without the use of aids and grade 5 of 5 of muscle power, or grade 2: ambulatory with aids or grade 4 of 5 of muscle power.

An analysis of secondary endpoints showed that the difference in ambulatory status grade 1 or 2 in the single- vs. multi-fraction group at week 1 was −0.4% (P value for noninferiority = .004), at week 4 it was −0.7% (P value for noninferiority = .01), and at week 12 it was 4.1% (P value for noninferiority = .002).

Overall survival rates at 12 weeks were 50% in the single-fraction group vs. 55% in the multi-fraction group; this difference was not statistically significant.

Of 11 other secondary endpoints analyzed, including ambulatory and safety endpoints, the between-group differences were not statistically significant or did not meet noninferiority criteria, the authors noted.

They concluded that although the trial did not meet the primary endpoint, ”the extent to which the lower bound of the CI overlapped with the noninferiority margin should be taken into account when interpreting the clinical importance of these findings.”

Cancer Research UK and Cancer Council Queensland funded the trial. Dr. Hoskin reported being supported by the National Institute for Health Research Manchester Biomedical Research Centre.

SOURCE: Hoskin PJ et al. JAMA 2019 Dec 3. doi: 10.1001/jama.2019.17913.

Single-fraction radiation could not be shown to be noninferior to multi-fraction radiation at improving walking function in patients with spinal compression from metastatic cancer, but the small differences seen in a noninferiority trial may not matter to patients, investigators suggest.

Among 686 patients with spinal compression from metastatic cancer randomly assigned in a clinical trial to receive either 8 Gy of radiation in a single fraction or 20 Gy delivered in 5 fractions over 5 consecutive days, 69.3% of patients in the single-fraction arm had good ambulatory status at 8 weeks, compared with 72.7% of patients in the multi-fraction arm (P for noninferiority = .06), reported Peter J Hoskin, BSc, MBBS, MD, of Mount Vernon Cancer Centre in Northwood, England, and colleagues.

The trial did not meet the endpoint of noninferiority of single-fraction radiation for improving ambulation at 8 weeks because the lower limit of the 95% confidence interval (CI) was –11.5%, overlapping the noninferiority margin of –11%.

“However, for all other time points, the CI limits were within the noninferiority margin, and the observed risk differences between single-fraction and multi-fraction radiotherapy groups in ambulatory status were small and unlikely to be of clinical importance,” the investigators wrote in JAMA.

The authors note that although radiotherapy is widely used as a palliative measure for patients with spinal canal compression caused my metastatic disease, there is no agreement on the optimum schedule, with some guidelines recommending higher doses in multiple fractions, and others recommending a single 8 Gy does for patients with painful spinal sites.

To see whether single-fraction radiation could be noninferior to multi-fraction, the investigators enrolled patients in 42 sites in the United Kingdom and 5 in Australia into the SCORAD trial, and randomly assigned them to either single-fraction (345 patients) or multi-fraction (341 patients) radiation. The median age of those enrolled was 70 years, and 44% had prostate cancer, 19% had lung cancer, and 12% had breast cancer.

As noted, the primary endpoint of noninferiority of single-fraction radiation at improving ambulatory status at week 8 was not met. Ambulatory status was based on a 4-point scale and was classified as either grade 1: ambulatory without the use of aids and grade 5 of 5 of muscle power, or grade 2: ambulatory with aids or grade 4 of 5 of muscle power.

An analysis of secondary endpoints showed that the difference in ambulatory status grade 1 or 2 in the single- vs. multi-fraction group at week 1 was −0.4% (P value for noninferiority = .004), at week 4 it was −0.7% (P value for noninferiority = .01), and at week 12 it was 4.1% (P value for noninferiority = .002).

Overall survival rates at 12 weeks were 50% in the single-fraction group vs. 55% in the multi-fraction group; this difference was not statistically significant.

Of 11 other secondary endpoints analyzed, including ambulatory and safety endpoints, the between-group differences were not statistically significant or did not meet noninferiority criteria, the authors noted.

They concluded that although the trial did not meet the primary endpoint, ”the extent to which the lower bound of the CI overlapped with the noninferiority margin should be taken into account when interpreting the clinical importance of these findings.”

Cancer Research UK and Cancer Council Queensland funded the trial. Dr. Hoskin reported being supported by the National Institute for Health Research Manchester Biomedical Research Centre.

SOURCE: Hoskin PJ et al. JAMA 2019 Dec 3. doi: 10.1001/jama.2019.17913.

Single-fraction radiation could not be shown to be noninferior to multi-fraction radiation at improving walking function in patients with spinal compression from metastatic cancer, but the small differences seen in a noninferiority trial may not matter to patients, investigators suggest.

Among 686 patients with spinal compression from metastatic cancer randomly assigned in a clinical trial to receive either 8 Gy of radiation in a single fraction or 20 Gy delivered in 5 fractions over 5 consecutive days, 69.3% of patients in the single-fraction arm had good ambulatory status at 8 weeks, compared with 72.7% of patients in the multi-fraction arm (P for noninferiority = .06), reported Peter J Hoskin, BSc, MBBS, MD, of Mount Vernon Cancer Centre in Northwood, England, and colleagues.

The trial did not meet the endpoint of noninferiority of single-fraction radiation for improving ambulation at 8 weeks because the lower limit of the 95% confidence interval (CI) was –11.5%, overlapping the noninferiority margin of –11%.

“However, for all other time points, the CI limits were within the noninferiority margin, and the observed risk differences between single-fraction and multi-fraction radiotherapy groups in ambulatory status were small and unlikely to be of clinical importance,” the investigators wrote in JAMA.

The authors note that although radiotherapy is widely used as a palliative measure for patients with spinal canal compression caused my metastatic disease, there is no agreement on the optimum schedule, with some guidelines recommending higher doses in multiple fractions, and others recommending a single 8 Gy does for patients with painful spinal sites.

To see whether single-fraction radiation could be noninferior to multi-fraction, the investigators enrolled patients in 42 sites in the United Kingdom and 5 in Australia into the SCORAD trial, and randomly assigned them to either single-fraction (345 patients) or multi-fraction (341 patients) radiation. The median age of those enrolled was 70 years, and 44% had prostate cancer, 19% had lung cancer, and 12% had breast cancer.

As noted, the primary endpoint of noninferiority of single-fraction radiation at improving ambulatory status at week 8 was not met. Ambulatory status was based on a 4-point scale and was classified as either grade 1: ambulatory without the use of aids and grade 5 of 5 of muscle power, or grade 2: ambulatory with aids or grade 4 of 5 of muscle power.

An analysis of secondary endpoints showed that the difference in ambulatory status grade 1 or 2 in the single- vs. multi-fraction group at week 1 was −0.4% (P value for noninferiority = .004), at week 4 it was −0.7% (P value for noninferiority = .01), and at week 12 it was 4.1% (P value for noninferiority = .002).

Overall survival rates at 12 weeks were 50% in the single-fraction group vs. 55% in the multi-fraction group; this difference was not statistically significant.

Of 11 other secondary endpoints analyzed, including ambulatory and safety endpoints, the between-group differences were not statistically significant or did not meet noninferiority criteria, the authors noted.

They concluded that although the trial did not meet the primary endpoint, ”the extent to which the lower bound of the CI overlapped with the noninferiority margin should be taken into account when interpreting the clinical importance of these findings.”

Cancer Research UK and Cancer Council Queensland funded the trial. Dr. Hoskin reported being supported by the National Institute for Health Research Manchester Biomedical Research Centre.

SOURCE: Hoskin PJ et al. JAMA 2019 Dec 3. doi: 10.1001/jama.2019.17913.

The use of supplemental MRI screening in women with extremely dense breast tissue and normal results on mammography led to the diagnosis of significantly fewer interval cancers, compared with mammography alone during a 2-year screening period, results from a randomized trial show.

Dr. Cecil Fox/National Cancer Institute

“Women with extremely dense breast tissue have an increased risk of breast cancer, and their cancers are also less likely to be detected on mammography,” Dutch researchers led by Marije F. Bakker, PhD, of Utrecht (The Netherlands) University and colleagues wrote for the Dense Tissue and Early Breast Neoplasm Screening (DENSE) Trial Study Group in an article published in the New England Journal of Medicine.

“Such patients may benefit from a tailored breast-screening strategy, supplemented with more sensitive imaging methods. The benefit of supplemental imaging is the subject of a worldwide debate. In the United States, a federal law directs breast-density reporting, but supplemental screening is not recommended in American guidelines. Although supplemental imaging increases the rate of cancer detection in women with dense breasts, the question remains whether it improves health outcomes,” they said.

In the DENSE trial, researchers assigned 40,373 women with extremely dense breast tissue and negative results on screening mammography to a group that was invited to undergo supplemental MRI or to a group that received mammography screening only. The women were between the ages of 50 and 75 years and were enrolled between December 2011 and November 2015 as part of the Dutch population-based digital mammography screening program. The primary outcome was the between-group difference in the incidence of interval cancers during a 2-year screening period.

Dr. Bakker and associates found that the interval cancer rate was 2.5 per 1,000 screenings among 4,783 women in the MRI invitation group, compared with 5 per 1,000 among the 32,312 women in the mammography-only group, a difference of 2.5 per 1,000 screenings (P less than 0.001). Among the women who were invited to undergo MRI, 59% actually underwent the procedure. Of the 20 interval cancers diagnosed in the MRI-invitation group, 4 were diagnosed in the women who had undergone MRI, which translated to 0.8 per 1,000 screenings. The remaining 16 were diagnosed in those who had not undergone MRI, which translated into 4.9 per 1,000 screenings.

“Undergoing supplemental MRI was associated with a cancer-detection rate of 16.5 per 1,000 screenings and resulted in a false positive rate of 8.0% (79.8 per 1,000 screenings),” the researchers wrote. “Of the women who underwent a breast biopsy on the basis of an MRI indication, 26.3% had breast cancer and 73.7% did not.”

Dr. Bakker and coauthors acknowledged certain limitations of the trial, including the fact that it was not large enough to examine the effect of MRI screening on breast cancer–specific or overall mortality. “This outcome would require a much larger sample size and longer follow-up,” they wrote. “The lower rate of interval cancers that we found among participants who underwent MRI is indicative of and prerequisite for an effect on mortality. After that, a reduction in the number of advanced cancers would also be required to show a mortality benefit, which would require several years of follow-up.”

In an accompanying editorial, Dan L. Longo, MD, noted that the study provides high-quality data from a randomized trial where none existed (N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMe1912943). “It appears to show that among women with dense breasts, the risk of interval cancers is halved by following a negative mammogram with MRI screening,” wrote Dr. Longo, who is deputy editor of the New England Journal of Medicine, as well as professor of medicine at Harvard Medical School, Boston. “But is a reduction in interval cancers an appropriate surrogate for improved overall survival? It appears that most of the cancers that were detected on supplemental MRI screening were found at an early stage. Ductal carcinoma in situ was 10 times more frequent among patients undergoing MRI, and these diagnoses were likely to lead to treatments. What remains unclear is whether the tumors would never otherwise have been detected or threatened the patient’s survival.”

The trial was supported by the University Medical Center Utrecht (the Netherlands), the Netherlands Organization for Health Research and Development, the Dutch Cancer Society, the Dutch Pink Ribbon–A Sister’s Hope organization, Stichting Kankerpreventie Midden-West, and Bayer Pharmaceuticals, with an in-kind contribution from Volpara Health Technologies.

The researchers reported having no relevant financial disclosures other than the trial funding. Dr. Longo is employed by the New England Journal of Medicine as deputy editor.
 

[email protected]

SOURCE: Bakker MF et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1903986.

The use of supplemental MRI screening in women with extremely dense breast tissue and normal results on mammography led to the diagnosis of significantly fewer interval cancers, compared with mammography alone during a 2-year screening period, results from a randomized trial show.

Dr. Cecil Fox/National Cancer Institute

“Women with extremely dense breast tissue have an increased risk of breast cancer, and their cancers are also less likely to be detected on mammography,” Dutch researchers led by Marije F. Bakker, PhD, of Utrecht (The Netherlands) University and colleagues wrote for the Dense Tissue and Early Breast Neoplasm Screening (DENSE) Trial Study Group in an article published in the New England Journal of Medicine.

“Such patients may benefit from a tailored breast-screening strategy, supplemented with more sensitive imaging methods. The benefit of supplemental imaging is the subject of a worldwide debate. In the United States, a federal law directs breast-density reporting, but supplemental screening is not recommended in American guidelines. Although supplemental imaging increases the rate of cancer detection in women with dense breasts, the question remains whether it improves health outcomes,” they said.

In the DENSE trial, researchers assigned 40,373 women with extremely dense breast tissue and negative results on screening mammography to a group that was invited to undergo supplemental MRI or to a group that received mammography screening only. The women were between the ages of 50 and 75 years and were enrolled between December 2011 and November 2015 as part of the Dutch population-based digital mammography screening program. The primary outcome was the between-group difference in the incidence of interval cancers during a 2-year screening period.

Dr. Bakker and associates found that the interval cancer rate was 2.5 per 1,000 screenings among 4,783 women in the MRI invitation group, compared with 5 per 1,000 among the 32,312 women in the mammography-only group, a difference of 2.5 per 1,000 screenings (P less than 0.001). Among the women who were invited to undergo MRI, 59% actually underwent the procedure. Of the 20 interval cancers diagnosed in the MRI-invitation group, 4 were diagnosed in the women who had undergone MRI, which translated to 0.8 per 1,000 screenings. The remaining 16 were diagnosed in those who had not undergone MRI, which translated into 4.9 per 1,000 screenings.

“Undergoing supplemental MRI was associated with a cancer-detection rate of 16.5 per 1,000 screenings and resulted in a false positive rate of 8.0% (79.8 per 1,000 screenings),” the researchers wrote. “Of the women who underwent a breast biopsy on the basis of an MRI indication, 26.3% had breast cancer and 73.7% did not.”

Dr. Bakker and coauthors acknowledged certain limitations of the trial, including the fact that it was not large enough to examine the effect of MRI screening on breast cancer–specific or overall mortality. “This outcome would require a much larger sample size and longer follow-up,” they wrote. “The lower rate of interval cancers that we found among participants who underwent MRI is indicative of and prerequisite for an effect on mortality. After that, a reduction in the number of advanced cancers would also be required to show a mortality benefit, which would require several years of follow-up.”

In an accompanying editorial, Dan L. Longo, MD, noted that the study provides high-quality data from a randomized trial where none existed (N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMe1912943). “It appears to show that among women with dense breasts, the risk of interval cancers is halved by following a negative mammogram with MRI screening,” wrote Dr. Longo, who is deputy editor of the New England Journal of Medicine, as well as professor of medicine at Harvard Medical School, Boston. “But is a reduction in interval cancers an appropriate surrogate for improved overall survival? It appears that most of the cancers that were detected on supplemental MRI screening were found at an early stage. Ductal carcinoma in situ was 10 times more frequent among patients undergoing MRI, and these diagnoses were likely to lead to treatments. What remains unclear is whether the tumors would never otherwise have been detected or threatened the patient’s survival.”

The trial was supported by the University Medical Center Utrecht (the Netherlands), the Netherlands Organization for Health Research and Development, the Dutch Cancer Society, the Dutch Pink Ribbon–A Sister’s Hope organization, Stichting Kankerpreventie Midden-West, and Bayer Pharmaceuticals, with an in-kind contribution from Volpara Health Technologies.

The researchers reported having no relevant financial disclosures other than the trial funding. Dr. Longo is employed by the New England Journal of Medicine as deputy editor.
 

[email protected]

SOURCE: Bakker MF et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1903986.

The use of supplemental MRI screening in women with extremely dense breast tissue and normal results on mammography led to the diagnosis of significantly fewer interval cancers, compared with mammography alone during a 2-year screening period, results from a randomized trial show.

Dr. Cecil Fox/National Cancer Institute

“Women with extremely dense breast tissue have an increased risk of breast cancer, and their cancers are also less likely to be detected on mammography,” Dutch researchers led by Marije F. Bakker, PhD, of Utrecht (The Netherlands) University and colleagues wrote for the Dense Tissue and Early Breast Neoplasm Screening (DENSE) Trial Study Group in an article published in the New England Journal of Medicine.

“Such patients may benefit from a tailored breast-screening strategy, supplemented with more sensitive imaging methods. The benefit of supplemental imaging is the subject of a worldwide debate. In the United States, a federal law directs breast-density reporting, but supplemental screening is not recommended in American guidelines. Although supplemental imaging increases the rate of cancer detection in women with dense breasts, the question remains whether it improves health outcomes,” they said.

In the DENSE trial, researchers assigned 40,373 women with extremely dense breast tissue and negative results on screening mammography to a group that was invited to undergo supplemental MRI or to a group that received mammography screening only. The women were between the ages of 50 and 75 years and were enrolled between December 2011 and November 2015 as part of the Dutch population-based digital mammography screening program. The primary outcome was the between-group difference in the incidence of interval cancers during a 2-year screening period.

Dr. Bakker and associates found that the interval cancer rate was 2.5 per 1,000 screenings among 4,783 women in the MRI invitation group, compared with 5 per 1,000 among the 32,312 women in the mammography-only group, a difference of 2.5 per 1,000 screenings (P less than 0.001). Among the women who were invited to undergo MRI, 59% actually underwent the procedure. Of the 20 interval cancers diagnosed in the MRI-invitation group, 4 were diagnosed in the women who had undergone MRI, which translated to 0.8 per 1,000 screenings. The remaining 16 were diagnosed in those who had not undergone MRI, which translated into 4.9 per 1,000 screenings.

“Undergoing supplemental MRI was associated with a cancer-detection rate of 16.5 per 1,000 screenings and resulted in a false positive rate of 8.0% (79.8 per 1,000 screenings),” the researchers wrote. “Of the women who underwent a breast biopsy on the basis of an MRI indication, 26.3% had breast cancer and 73.7% did not.”

Dr. Bakker and coauthors acknowledged certain limitations of the trial, including the fact that it was not large enough to examine the effect of MRI screening on breast cancer–specific or overall mortality. “This outcome would require a much larger sample size and longer follow-up,” they wrote. “The lower rate of interval cancers that we found among participants who underwent MRI is indicative of and prerequisite for an effect on mortality. After that, a reduction in the number of advanced cancers would also be required to show a mortality benefit, which would require several years of follow-up.”

In an accompanying editorial, Dan L. Longo, MD, noted that the study provides high-quality data from a randomized trial where none existed (N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMe1912943). “It appears to show that among women with dense breasts, the risk of interval cancers is halved by following a negative mammogram with MRI screening,” wrote Dr. Longo, who is deputy editor of the New England Journal of Medicine, as well as professor of medicine at Harvard Medical School, Boston. “But is a reduction in interval cancers an appropriate surrogate for improved overall survival? It appears that most of the cancers that were detected on supplemental MRI screening were found at an early stage. Ductal carcinoma in situ was 10 times more frequent among patients undergoing MRI, and these diagnoses were likely to lead to treatments. What remains unclear is whether the tumors would never otherwise have been detected or threatened the patient’s survival.”

The trial was supported by the University Medical Center Utrecht (the Netherlands), the Netherlands Organization for Health Research and Development, the Dutch Cancer Society, the Dutch Pink Ribbon–A Sister’s Hope organization, Stichting Kankerpreventie Midden-West, and Bayer Pharmaceuticals, with an in-kind contribution from Volpara Health Technologies.

The researchers reported having no relevant financial disclosures other than the trial funding. Dr. Longo is employed by the New England Journal of Medicine as deputy editor.
 

[email protected]

SOURCE: Bakker MF et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1903986.

Breast cancer survivors may have a lower prevalence of cardiac risk factors at the time of first myocardial infarction and better outcomes compared with those having a first MI from the general population, according to findings from a retrospective study.

In addition, women without breast cancer were younger at the time of first MI compared with survivors, wrote Srikanth Yandrapalli, MD, of New York Medical College, Valhalla, and colleagues. Their report is in the American Journal of Medicine.

The researchers identified 1,644,032 women with a first MI, 56,842 of whom were breast cancer survivors. The team evaluated differences in the prevalence of cardiac risk factors and related outcomes in breast cancer survivors in comparison to the general population.

At baseline, the mean age of subjects with a history of breast cancer was 77 years (range, 11 years), while the mean age of women without breast cancer was 71 years (range, 15 years).

Clinical data were collected from the United States National Inpatient Sample for January 2005 to September 2015. Other outcomes assessed were differences in baseline characteristics and the rate of in-hospital mortality in both groups.

After analysis, the researchers found that breast cancer survivors had a lower prevalence of diabetes mellitus (30.1% vs. 33.1%), obesity (9.4% vs. 13.0%), and smoking (24.1% vs. 27.0%), but higher rates of dyslipidemia (52.7% vs. 48.4%) and hypertension (73.6% vs. 68.1%), compared with women without breast cancer (All P less than .001).

With respect to age, women without breast cancer were 6 years younger than breast cancer survivors at the time of first acute MI (mean age, 71 vs. 77 years; P less than .001).

In addition, the rate of in-hospital mortality was higher in women without breast cancer (7.9%) compared with survivors (7.1%) (P less than .001). After risk adjustment, these results remained unchanged (odds ratio, 0.89; 95% confidence interval, 0.82-0.94).

“Breast cancer survivors in the U.S. are at least 6 years older than the general population of women without breast cancer, and they had a favorable cardiac risk factor profile at the time of first myocardial infarction,” Dr. Yandrapalli and colleagues explained. “The reason for these findings are unclear and hypothesis generating,” they added.

The researchers acknowledged that a key limitation of the study was the retrospective design. As a result, the potential effects of residual confounding should be considered when interpreting the results.

“The favorable impact of health education and participation in cancer survivorship programs on these observed differences in breast cancer survivors should be further explored,” they concluded.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: Yandrapalli S et al. Am J Med. 2019 Nov 9. doi: 10.1016/j.amjmed.2019.10.018.

Breast cancer survivors may have a lower prevalence of cardiac risk factors at the time of first myocardial infarction and better outcomes compared with those having a first MI from the general population, according to findings from a retrospective study.

In addition, women without breast cancer were younger at the time of first MI compared with survivors, wrote Srikanth Yandrapalli, MD, of New York Medical College, Valhalla, and colleagues. Their report is in the American Journal of Medicine.

The researchers identified 1,644,032 women with a first MI, 56,842 of whom were breast cancer survivors. The team evaluated differences in the prevalence of cardiac risk factors and related outcomes in breast cancer survivors in comparison to the general population.

At baseline, the mean age of subjects with a history of breast cancer was 77 years (range, 11 years), while the mean age of women without breast cancer was 71 years (range, 15 years).

Clinical data were collected from the United States National Inpatient Sample for January 2005 to September 2015. Other outcomes assessed were differences in baseline characteristics and the rate of in-hospital mortality in both groups.

After analysis, the researchers found that breast cancer survivors had a lower prevalence of diabetes mellitus (30.1% vs. 33.1%), obesity (9.4% vs. 13.0%), and smoking (24.1% vs. 27.0%), but higher rates of dyslipidemia (52.7% vs. 48.4%) and hypertension (73.6% vs. 68.1%), compared with women without breast cancer (All P less than .001).

With respect to age, women without breast cancer were 6 years younger than breast cancer survivors at the time of first acute MI (mean age, 71 vs. 77 years; P less than .001).

In addition, the rate of in-hospital mortality was higher in women without breast cancer (7.9%) compared with survivors (7.1%) (P less than .001). After risk adjustment, these results remained unchanged (odds ratio, 0.89; 95% confidence interval, 0.82-0.94).

“Breast cancer survivors in the U.S. are at least 6 years older than the general population of women without breast cancer, and they had a favorable cardiac risk factor profile at the time of first myocardial infarction,” Dr. Yandrapalli and colleagues explained. “The reason for these findings are unclear and hypothesis generating,” they added.

The researchers acknowledged that a key limitation of the study was the retrospective design. As a result, the potential effects of residual confounding should be considered when interpreting the results.

“The favorable impact of health education and participation in cancer survivorship programs on these observed differences in breast cancer survivors should be further explored,” they concluded.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: Yandrapalli S et al. Am J Med. 2019 Nov 9. doi: 10.1016/j.amjmed.2019.10.018.

Breast cancer survivors may have a lower prevalence of cardiac risk factors at the time of first myocardial infarction and better outcomes compared with those having a first MI from the general population, according to findings from a retrospective study.

In addition, women without breast cancer were younger at the time of first MI compared with survivors, wrote Srikanth Yandrapalli, MD, of New York Medical College, Valhalla, and colleagues. Their report is in the American Journal of Medicine.

The researchers identified 1,644,032 women with a first MI, 56,842 of whom were breast cancer survivors. The team evaluated differences in the prevalence of cardiac risk factors and related outcomes in breast cancer survivors in comparison to the general population.

At baseline, the mean age of subjects with a history of breast cancer was 77 years (range, 11 years), while the mean age of women without breast cancer was 71 years (range, 15 years).

Clinical data were collected from the United States National Inpatient Sample for January 2005 to September 2015. Other outcomes assessed were differences in baseline characteristics and the rate of in-hospital mortality in both groups.

After analysis, the researchers found that breast cancer survivors had a lower prevalence of diabetes mellitus (30.1% vs. 33.1%), obesity (9.4% vs. 13.0%), and smoking (24.1% vs. 27.0%), but higher rates of dyslipidemia (52.7% vs. 48.4%) and hypertension (73.6% vs. 68.1%), compared with women without breast cancer (All P less than .001).

With respect to age, women without breast cancer were 6 years younger than breast cancer survivors at the time of first acute MI (mean age, 71 vs. 77 years; P less than .001).

In addition, the rate of in-hospital mortality was higher in women without breast cancer (7.9%) compared with survivors (7.1%) (P less than .001). After risk adjustment, these results remained unchanged (odds ratio, 0.89; 95% confidence interval, 0.82-0.94).

“Breast cancer survivors in the U.S. are at least 6 years older than the general population of women without breast cancer, and they had a favorable cardiac risk factor profile at the time of first myocardial infarction,” Dr. Yandrapalli and colleagues explained. “The reason for these findings are unclear and hypothesis generating,” they added.

The researchers acknowledged that a key limitation of the study was the retrospective design. As a result, the potential effects of residual confounding should be considered when interpreting the results.

“The favorable impact of health education and participation in cancer survivorship programs on these observed differences in breast cancer survivors should be further explored,” they concluded.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: Yandrapalli S et al. Am J Med. 2019 Nov 9. doi: 10.1016/j.amjmed.2019.10.018.

NATIONAL HARBOR, MD – PRS-343, a 4-1BB/HER2 bispecific molecule, has demonstrated safety and antitumor activity in patients with heavily pretreated, HER2-positive solid tumors, an investigator reported at the annual meeting of the Society for Immunotherapy of Cancer.

In a phase 1 trial of 18 evaluable patients, PRS-343 produced partial responses in 2 patients and enabled 8 patients to maintain stable disease. PRS-343 was considered well tolerated at all doses and schedules tested.

“PRS-343 is a bispecific construct targeting HER2 as well as 4-1BB,” said Geoffrey Y. Ku, MD, of Memorial Sloan Kettering Cancer Center in New York. “The HER2 component of the molecule localizes it into the tumor microenvironment of any HER2-positive cells. If the density of the HER2 protein is high enough, that facilitates cross-linkage of 4-1BB.

“4-1BB is an immune agonist that’s present in activated T cells, and cross-linkage helps to improve T-cell exhaustion and is also critical for T-cell expansion. The idea is that, by localizing 4-1BB activation to the tumor microenvironment, we can avoid some of the systemic toxicities associated with naked 4-1BB antibodies,” Dr. Ku added.

The ongoing, phase 1 trial of PRS-343 (NCT03330561) has enrolled 53 patients with a range of HER2-positive malignancies. To be eligible, patients must have progressed on standard therapy or have a tumor for which no standard therapy is available.

The most common diagnosis among enrolled patients is gastroesophageal cancer (n = 19), followed by breast cancer (n = 14), gynecologic cancers (n = 6), colorectal cancer (n = 5), and other malignancies.

The patients’ median age at baseline was 61 years (range, 29-92 years), and a majority were female (62%). Most patients (79%) had received three or more prior lines of therapy, including anti-HER2 treatments. Breast cancer patients had received a median of four anti-HER2 treatments, and gastric cancer patients had received a median of two.

The patients have been treated with PRS-343 at 11 dose levels, ranging from 0.0005 mg/kg to 8 mg/kg, given every 3 weeks. The highest dose, 8 mg/kg, was also given every 2 weeks.

Treatment-related adverse events (TRAEs) included infusion-related reactions (9%), fatigue (9%), chills (6%), flushing (6%), nausea (6%), diarrhea (6%), vomiting (5%), and noncardiac chest pain (4%).

“This was an extremely well-tolerated drug,” Dr. Ku said. “Out of 111 TRAEs, only a tiny proportion were grade 3, and toxicities mostly clustered around infusion-related reactions, constitutional symptoms, as well as gastrointestinal symptoms.”

Grade 3 TRAEs included infusion-related reactions (2%), fatigue (1%), flushing (3%), and noncardiac chest pain (1%). There were no grade 4-5 TRAEs.

At the data cutoff (Oct. 23, 2019), 18 patients were evaluable for a response at active dose levels (2.5 mg/kg, 5 mg/kg, and 8 mg/kg).

Two patients achieved a partial response, and eight had stable disease. “This translates to a response rate of 11% and a disease control rate of 55%,” Dr. Ku noted.

Both responders received PRS-343 at 8 mg/kg every 2 weeks. One of these patients had stage 4 gastric adenocarcinoma, and one had stage 4 gynecologic carcinoma.

Of the eight patients with stable disease, three received PRS-343 at 8 mg/kg every 2 weeks, two received 8 mg/kg every 3 weeks, one received the 5 mg/kg dose, and two received the 2.5 mg/kg dose.

Dr. Ku noted that the average time on treatment significantly increased in patients who received PRS-343 at 8 mg/kg every 2 weeks. Additionally, both responders and patients with stable disease had a “clear increase” in CD8+ T cells.

“[PRS-343] has demonstrated antitumor activity in heavily pretreated patients across multiple tumor types, and the treatment history, specifically the receipt of prior anti-HER2 therapy, indicates this is a 4-1BB-driven mechanism of action,” Dr. Ku said. “Based on these results, future studies are planned for continued development in defined HER2-positive indications.”

The current study is sponsored by Pieris Pharmaceuticals. Dr. Ku disclosed relationships with Arog Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck, Zymeworks, and Pieris Pharmaceuticals.

SOURCE: Ku GY et al. SITC 2019, Abstract O82.
 

NATIONAL HARBOR, MD – PRS-343, a 4-1BB/HER2 bispecific molecule, has demonstrated safety and antitumor activity in patients with heavily pretreated, HER2-positive solid tumors, an investigator reported at the annual meeting of the Society for Immunotherapy of Cancer.

In a phase 1 trial of 18 evaluable patients, PRS-343 produced partial responses in 2 patients and enabled 8 patients to maintain stable disease. PRS-343 was considered well tolerated at all doses and schedules tested.

“PRS-343 is a bispecific construct targeting HER2 as well as 4-1BB,” said Geoffrey Y. Ku, MD, of Memorial Sloan Kettering Cancer Center in New York. “The HER2 component of the molecule localizes it into the tumor microenvironment of any HER2-positive cells. If the density of the HER2 protein is high enough, that facilitates cross-linkage of 4-1BB.

“4-1BB is an immune agonist that’s present in activated T cells, and cross-linkage helps to improve T-cell exhaustion and is also critical for T-cell expansion. The idea is that, by localizing 4-1BB activation to the tumor microenvironment, we can avoid some of the systemic toxicities associated with naked 4-1BB antibodies,” Dr. Ku added.

The ongoing, phase 1 trial of PRS-343 (NCT03330561) has enrolled 53 patients with a range of HER2-positive malignancies. To be eligible, patients must have progressed on standard therapy or have a tumor for which no standard therapy is available.

The most common diagnosis among enrolled patients is gastroesophageal cancer (n = 19), followed by breast cancer (n = 14), gynecologic cancers (n = 6), colorectal cancer (n = 5), and other malignancies.

The patients’ median age at baseline was 61 years (range, 29-92 years), and a majority were female (62%). Most patients (79%) had received three or more prior lines of therapy, including anti-HER2 treatments. Breast cancer patients had received a median of four anti-HER2 treatments, and gastric cancer patients had received a median of two.

The patients have been treated with PRS-343 at 11 dose levels, ranging from 0.0005 mg/kg to 8 mg/kg, given every 3 weeks. The highest dose, 8 mg/kg, was also given every 2 weeks.

Treatment-related adverse events (TRAEs) included infusion-related reactions (9%), fatigue (9%), chills (6%), flushing (6%), nausea (6%), diarrhea (6%), vomiting (5%), and noncardiac chest pain (4%).

“This was an extremely well-tolerated drug,” Dr. Ku said. “Out of 111 TRAEs, only a tiny proportion were grade 3, and toxicities mostly clustered around infusion-related reactions, constitutional symptoms, as well as gastrointestinal symptoms.”

Grade 3 TRAEs included infusion-related reactions (2%), fatigue (1%), flushing (3%), and noncardiac chest pain (1%). There were no grade 4-5 TRAEs.

At the data cutoff (Oct. 23, 2019), 18 patients were evaluable for a response at active dose levels (2.5 mg/kg, 5 mg/kg, and 8 mg/kg).

Two patients achieved a partial response, and eight had stable disease. “This translates to a response rate of 11% and a disease control rate of 55%,” Dr. Ku noted.

Both responders received PRS-343 at 8 mg/kg every 2 weeks. One of these patients had stage 4 gastric adenocarcinoma, and one had stage 4 gynecologic carcinoma.

Of the eight patients with stable disease, three received PRS-343 at 8 mg/kg every 2 weeks, two received 8 mg/kg every 3 weeks, one received the 5 mg/kg dose, and two received the 2.5 mg/kg dose.

Dr. Ku noted that the average time on treatment significantly increased in patients who received PRS-343 at 8 mg/kg every 2 weeks. Additionally, both responders and patients with stable disease had a “clear increase” in CD8+ T cells.

“[PRS-343] has demonstrated antitumor activity in heavily pretreated patients across multiple tumor types, and the treatment history, specifically the receipt of prior anti-HER2 therapy, indicates this is a 4-1BB-driven mechanism of action,” Dr. Ku said. “Based on these results, future studies are planned for continued development in defined HER2-positive indications.”

The current study is sponsored by Pieris Pharmaceuticals. Dr. Ku disclosed relationships with Arog Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck, Zymeworks, and Pieris Pharmaceuticals.

SOURCE: Ku GY et al. SITC 2019, Abstract O82.
 

NATIONAL HARBOR, MD – PRS-343, a 4-1BB/HER2 bispecific molecule, has demonstrated safety and antitumor activity in patients with heavily pretreated, HER2-positive solid tumors, an investigator reported at the annual meeting of the Society for Immunotherapy of Cancer.

In a phase 1 trial of 18 evaluable patients, PRS-343 produced partial responses in 2 patients and enabled 8 patients to maintain stable disease. PRS-343 was considered well tolerated at all doses and schedules tested.

“PRS-343 is a bispecific construct targeting HER2 as well as 4-1BB,” said Geoffrey Y. Ku, MD, of Memorial Sloan Kettering Cancer Center in New York. “The HER2 component of the molecule localizes it into the tumor microenvironment of any HER2-positive cells. If the density of the HER2 protein is high enough, that facilitates cross-linkage of 4-1BB.

“4-1BB is an immune agonist that’s present in activated T cells, and cross-linkage helps to improve T-cell exhaustion and is also critical for T-cell expansion. The idea is that, by localizing 4-1BB activation to the tumor microenvironment, we can avoid some of the systemic toxicities associated with naked 4-1BB antibodies,” Dr. Ku added.

The ongoing, phase 1 trial of PRS-343 (NCT03330561) has enrolled 53 patients with a range of HER2-positive malignancies. To be eligible, patients must have progressed on standard therapy or have a tumor for which no standard therapy is available.

The most common diagnosis among enrolled patients is gastroesophageal cancer (n = 19), followed by breast cancer (n = 14), gynecologic cancers (n = 6), colorectal cancer (n = 5), and other malignancies.

The patients’ median age at baseline was 61 years (range, 29-92 years), and a majority were female (62%). Most patients (79%) had received three or more prior lines of therapy, including anti-HER2 treatments. Breast cancer patients had received a median of four anti-HER2 treatments, and gastric cancer patients had received a median of two.

The patients have been treated with PRS-343 at 11 dose levels, ranging from 0.0005 mg/kg to 8 mg/kg, given every 3 weeks. The highest dose, 8 mg/kg, was also given every 2 weeks.

Treatment-related adverse events (TRAEs) included infusion-related reactions (9%), fatigue (9%), chills (6%), flushing (6%), nausea (6%), diarrhea (6%), vomiting (5%), and noncardiac chest pain (4%).

“This was an extremely well-tolerated drug,” Dr. Ku said. “Out of 111 TRAEs, only a tiny proportion were grade 3, and toxicities mostly clustered around infusion-related reactions, constitutional symptoms, as well as gastrointestinal symptoms.”

Grade 3 TRAEs included infusion-related reactions (2%), fatigue (1%), flushing (3%), and noncardiac chest pain (1%). There were no grade 4-5 TRAEs.

At the data cutoff (Oct. 23, 2019), 18 patients were evaluable for a response at active dose levels (2.5 mg/kg, 5 mg/kg, and 8 mg/kg).

Two patients achieved a partial response, and eight had stable disease. “This translates to a response rate of 11% and a disease control rate of 55%,” Dr. Ku noted.

Both responders received PRS-343 at 8 mg/kg every 2 weeks. One of these patients had stage 4 gastric adenocarcinoma, and one had stage 4 gynecologic carcinoma.

Of the eight patients with stable disease, three received PRS-343 at 8 mg/kg every 2 weeks, two received 8 mg/kg every 3 weeks, one received the 5 mg/kg dose, and two received the 2.5 mg/kg dose.

Dr. Ku noted that the average time on treatment significantly increased in patients who received PRS-343 at 8 mg/kg every 2 weeks. Additionally, both responders and patients with stable disease had a “clear increase” in CD8+ T cells.

“[PRS-343] has demonstrated antitumor activity in heavily pretreated patients across multiple tumor types, and the treatment history, specifically the receipt of prior anti-HER2 therapy, indicates this is a 4-1BB-driven mechanism of action,” Dr. Ku said. “Based on these results, future studies are planned for continued development in defined HER2-positive indications.”

The current study is sponsored by Pieris Pharmaceuticals. Dr. Ku disclosed relationships with Arog Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck, Zymeworks, and Pieris Pharmaceuticals.

SOURCE: Ku GY et al. SITC 2019, Abstract O82.
 

In this edition of “How I will treat my next patient,” I highlight two studies that previously reported significant progression-free survival (PFS) improvements and more recently, at the European Society for Medical Oncology Congress, overall survival (OS) benefit. I reflect on the significance of these new reports in the wake of previously reported data and guidelines from the National Comprehensive Cancer Network (NCCN).

Osimertinib in advanced NSCLC

In the double-blind, phase 3 FLAURA trial, 556 patients with EGFR-mutated (EGFRm), advanced non–small cell lung cancer (NSCLC) received osimertinib or a standard tyrosine kinase inhibitor (TKI) as initial treatment. PFS, the primary endpoint, was clinically and statistically better for osimertinib (18.9 months vs. 10.2 months; hazard ratio 0.46; P less than .001), overall and in all major subgroups. There were fewer grade 3-4 adverse events and fewer permanent treatment discontinuations with osimertinib.

At the time of initial publication, OS data were immature, but because of the substantial survival improvements previously noted, osimertinib was approved by the Food and Drug Administration for first-line treatment of EGFRm stage IV NSCLC patients in April 2018 (N Engl J Med. 2018; 378:113-25).

More recently, at ESMO 2019, Suresh Ramalingam, MD, of the department of hematology and medical oncology at Emory University, Atlanta, and colleagues reported the OS results. Crossover to osimertinib was allowed for patients on the standard TKI arm when they had progressive disease and a T790M mutation. Osimertinib produced a median OS of 38.6 months, compared with 31.8 months for standard TKI (HR, 0.799; P = .0462), a 24-month OS rate of 74% vs. 59% (with no overlap in the 95% confidence intervals), and a 36-month OS rate of 54% vs. 44%. These benefits were interpreted to be statistically significant and clinically meaningful.

The 31.8-month median OS for standard TKI was competitive with the highest reported OS for standard therapy, perhaps because crossover to osimertinib was permitted.

What this means in clinical practice

The report by Dr. Ramalingam and colleagues – and the next abstract I will review – remind me of the famous “You had me at Hello” line from “Jerry Maguire.”

For patient education – and perhaps for some national regulatory agencies – it is good that we now have definition of what the average OS is with osimertinib, compared with standard TKI followed by osimertinib. However, very few oncologists in the United States likely use the latter strategy anymore. It was clear when the impressive PFS and toxicity information appeared in 2018 in the New England Journal of Medicine that osimertinib is the best tolerated, most durably effective front-line treatment for EGFRm mNSCLC, regardless of disease extent, sex, nationality, type of EGFRm (L858R amino acid substitution in exon 21 or exon 19 deletion), or presence/absence of central nervous system metastases.

In NCCN guidelines, osimertinib was listed as the preferred TKI, prior to the OS report at ESMO 2019. The challenges going forward will be to identify high-risk patient subsets who might benefit from drug combinations or novel new agents.

MONARCH 2: Abemaciclib plus fulvestrant

In the MONARCH 2, randomized, placebo-controlled, phase 3 trial, abemaciclib plus fulvestrant (abema-F) significantly improved PFS, in comparison with placebo plus fulvestrant (placebo-F; 16.9 months vs. 9.3 months; HR, 0.563) in 669 premenopausal (with concurrent ovarian function suppression) and postmenopausal women with metastatic breast cancer (mBC) who had disease progression on one to two lines of prior hormonal therapy (J Clin Oncol. 2017;35[25]:2875-84).

At ESMO 2019, George W. Sledge Jr., MD, of Stanford (Calif.) Medical Center, and colleagues reported the OS results, a secondary endpoint for the trial (JAMA Oncol. 2019 Sep 29. doi. 10.1001/jamaoncol.2019.4782). At the prespecified interim analysis point, median OS for abema-F was 46.7 months vs. 37.3 months for placebo-F (HR, 0.757; 95% CI 0.505-0.945; P = .0137). Patients with greatest benefit from abema-F were exactly the patients who needed the most help – those with visceral metastases (HR 0.675) and with primary resistance to prior hormonal therapy (HR, 0.686).

At 3 years, at least three times as many patients remained progression free with abema-F, compared with placebo-F, and the abema-F patients experienced prolongation in time to eventual chemotherapy (50.2 months vs. 22.1 months; HR, 0.625).

What this means in clinical practice

Many times I find myself sitting at the annual meeting of the American Society of Clinical Oncology and thinking, “Only a medical oncologist like me would find this result exciting.” Prior to ESMO 2019, MONARCH 2 (and a similar study presented at ESMO 2019, MONALEESA-3, which employed an alternative CDK 4/6 inhibitor, ribociclib, with similar OS results) added to the body of literature that caused NCCN guidelines to list all of the approved CDK 4/6 inhibitors plus endocrine therapy for first- or second-line use in patients with hormone-receptor positive, HER2/neu-negative mBC. NCCN guidelines have the caveat that, among patients with disease progression on CDK 4/6 inhibitors in the first-line setting, there are no data to support continuing the CDK 4/6 inhibitor or switching to an alternative CDK 4/6 inhibitor thereafter.

For that shrinking group of patients and doctors who choose to avoid CDK 4/6 inhibitors for first-line treatment, as we describe risks and benefits of using a CDK 4/6 inhibitor for second- or third-line therapy, we have high-quality OS information from ESMO 2019 to answer the “Is it worth it?” question.

Are the results of MONARCH 2 and MONALEESA-3 practice changing? No. We were already convinced. Should we be excited that we have this new information for discussions with our patients? Absolutely.
 

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I will treat my next patient,” I highlight two studies that previously reported significant progression-free survival (PFS) improvements and more recently, at the European Society for Medical Oncology Congress, overall survival (OS) benefit. I reflect on the significance of these new reports in the wake of previously reported data and guidelines from the National Comprehensive Cancer Network (NCCN).

Osimertinib in advanced NSCLC

In the double-blind, phase 3 FLAURA trial, 556 patients with EGFR-mutated (EGFRm), advanced non–small cell lung cancer (NSCLC) received osimertinib or a standard tyrosine kinase inhibitor (TKI) as initial treatment. PFS, the primary endpoint, was clinically and statistically better for osimertinib (18.9 months vs. 10.2 months; hazard ratio 0.46; P less than .001), overall and in all major subgroups. There were fewer grade 3-4 adverse events and fewer permanent treatment discontinuations with osimertinib.

At the time of initial publication, OS data were immature, but because of the substantial survival improvements previously noted, osimertinib was approved by the Food and Drug Administration for first-line treatment of EGFRm stage IV NSCLC patients in April 2018 (N Engl J Med. 2018; 378:113-25).

More recently, at ESMO 2019, Suresh Ramalingam, MD, of the department of hematology and medical oncology at Emory University, Atlanta, and colleagues reported the OS results. Crossover to osimertinib was allowed for patients on the standard TKI arm when they had progressive disease and a T790M mutation. Osimertinib produced a median OS of 38.6 months, compared with 31.8 months for standard TKI (HR, 0.799; P = .0462), a 24-month OS rate of 74% vs. 59% (with no overlap in the 95% confidence intervals), and a 36-month OS rate of 54% vs. 44%. These benefits were interpreted to be statistically significant and clinically meaningful.

The 31.8-month median OS for standard TKI was competitive with the highest reported OS for standard therapy, perhaps because crossover to osimertinib was permitted.

What this means in clinical practice

The report by Dr. Ramalingam and colleagues – and the next abstract I will review – remind me of the famous “You had me at Hello” line from “Jerry Maguire.”

For patient education – and perhaps for some national regulatory agencies – it is good that we now have definition of what the average OS is with osimertinib, compared with standard TKI followed by osimertinib. However, very few oncologists in the United States likely use the latter strategy anymore. It was clear when the impressive PFS and toxicity information appeared in 2018 in the New England Journal of Medicine that osimertinib is the best tolerated, most durably effective front-line treatment for EGFRm mNSCLC, regardless of disease extent, sex, nationality, type of EGFRm (L858R amino acid substitution in exon 21 or exon 19 deletion), or presence/absence of central nervous system metastases.

In NCCN guidelines, osimertinib was listed as the preferred TKI, prior to the OS report at ESMO 2019. The challenges going forward will be to identify high-risk patient subsets who might benefit from drug combinations or novel new agents.

MONARCH 2: Abemaciclib plus fulvestrant

In the MONARCH 2, randomized, placebo-controlled, phase 3 trial, abemaciclib plus fulvestrant (abema-F) significantly improved PFS, in comparison with placebo plus fulvestrant (placebo-F; 16.9 months vs. 9.3 months; HR, 0.563) in 669 premenopausal (with concurrent ovarian function suppression) and postmenopausal women with metastatic breast cancer (mBC) who had disease progression on one to two lines of prior hormonal therapy (J Clin Oncol. 2017;35[25]:2875-84).

At ESMO 2019, George W. Sledge Jr., MD, of Stanford (Calif.) Medical Center, and colleagues reported the OS results, a secondary endpoint for the trial (JAMA Oncol. 2019 Sep 29. doi. 10.1001/jamaoncol.2019.4782). At the prespecified interim analysis point, median OS for abema-F was 46.7 months vs. 37.3 months for placebo-F (HR, 0.757; 95% CI 0.505-0.945; P = .0137). Patients with greatest benefit from abema-F were exactly the patients who needed the most help – those with visceral metastases (HR 0.675) and with primary resistance to prior hormonal therapy (HR, 0.686).

At 3 years, at least three times as many patients remained progression free with abema-F, compared with placebo-F, and the abema-F patients experienced prolongation in time to eventual chemotherapy (50.2 months vs. 22.1 months; HR, 0.625).

What this means in clinical practice

Many times I find myself sitting at the annual meeting of the American Society of Clinical Oncology and thinking, “Only a medical oncologist like me would find this result exciting.” Prior to ESMO 2019, MONARCH 2 (and a similar study presented at ESMO 2019, MONALEESA-3, which employed an alternative CDK 4/6 inhibitor, ribociclib, with similar OS results) added to the body of literature that caused NCCN guidelines to list all of the approved CDK 4/6 inhibitors plus endocrine therapy for first- or second-line use in patients with hormone-receptor positive, HER2/neu-negative mBC. NCCN guidelines have the caveat that, among patients with disease progression on CDK 4/6 inhibitors in the first-line setting, there are no data to support continuing the CDK 4/6 inhibitor or switching to an alternative CDK 4/6 inhibitor thereafter.

For that shrinking group of patients and doctors who choose to avoid CDK 4/6 inhibitors for first-line treatment, as we describe risks and benefits of using a CDK 4/6 inhibitor for second- or third-line therapy, we have high-quality OS information from ESMO 2019 to answer the “Is it worth it?” question.

Are the results of MONARCH 2 and MONALEESA-3 practice changing? No. We were already convinced. Should we be excited that we have this new information for discussions with our patients? Absolutely.
 

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I will treat my next patient,” I highlight two studies that previously reported significant progression-free survival (PFS) improvements and more recently, at the European Society for Medical Oncology Congress, overall survival (OS) benefit. I reflect on the significance of these new reports in the wake of previously reported data and guidelines from the National Comprehensive Cancer Network (NCCN).

Osimertinib in advanced NSCLC

In the double-blind, phase 3 FLAURA trial, 556 patients with EGFR-mutated (EGFRm), advanced non–small cell lung cancer (NSCLC) received osimertinib or a standard tyrosine kinase inhibitor (TKI) as initial treatment. PFS, the primary endpoint, was clinically and statistically better for osimertinib (18.9 months vs. 10.2 months; hazard ratio 0.46; P less than .001), overall and in all major subgroups. There were fewer grade 3-4 adverse events and fewer permanent treatment discontinuations with osimertinib.

At the time of initial publication, OS data were immature, but because of the substantial survival improvements previously noted, osimertinib was approved by the Food and Drug Administration for first-line treatment of EGFRm stage IV NSCLC patients in April 2018 (N Engl J Med. 2018; 378:113-25).

More recently, at ESMO 2019, Suresh Ramalingam, MD, of the department of hematology and medical oncology at Emory University, Atlanta, and colleagues reported the OS results. Crossover to osimertinib was allowed for patients on the standard TKI arm when they had progressive disease and a T790M mutation. Osimertinib produced a median OS of 38.6 months, compared with 31.8 months for standard TKI (HR, 0.799; P = .0462), a 24-month OS rate of 74% vs. 59% (with no overlap in the 95% confidence intervals), and a 36-month OS rate of 54% vs. 44%. These benefits were interpreted to be statistically significant and clinically meaningful.

The 31.8-month median OS for standard TKI was competitive with the highest reported OS for standard therapy, perhaps because crossover to osimertinib was permitted.

What this means in clinical practice

The report by Dr. Ramalingam and colleagues – and the next abstract I will review – remind me of the famous “You had me at Hello” line from “Jerry Maguire.”

For patient education – and perhaps for some national regulatory agencies – it is good that we now have definition of what the average OS is with osimertinib, compared with standard TKI followed by osimertinib. However, very few oncologists in the United States likely use the latter strategy anymore. It was clear when the impressive PFS and toxicity information appeared in 2018 in the New England Journal of Medicine that osimertinib is the best tolerated, most durably effective front-line treatment for EGFRm mNSCLC, regardless of disease extent, sex, nationality, type of EGFRm (L858R amino acid substitution in exon 21 or exon 19 deletion), or presence/absence of central nervous system metastases.

In NCCN guidelines, osimertinib was listed as the preferred TKI, prior to the OS report at ESMO 2019. The challenges going forward will be to identify high-risk patient subsets who might benefit from drug combinations or novel new agents.

MONARCH 2: Abemaciclib plus fulvestrant

In the MONARCH 2, randomized, placebo-controlled, phase 3 trial, abemaciclib plus fulvestrant (abema-F) significantly improved PFS, in comparison with placebo plus fulvestrant (placebo-F; 16.9 months vs. 9.3 months; HR, 0.563) in 669 premenopausal (with concurrent ovarian function suppression) and postmenopausal women with metastatic breast cancer (mBC) who had disease progression on one to two lines of prior hormonal therapy (J Clin Oncol. 2017;35[25]:2875-84).

At ESMO 2019, George W. Sledge Jr., MD, of Stanford (Calif.) Medical Center, and colleagues reported the OS results, a secondary endpoint for the trial (JAMA Oncol. 2019 Sep 29. doi. 10.1001/jamaoncol.2019.4782). At the prespecified interim analysis point, median OS for abema-F was 46.7 months vs. 37.3 months for placebo-F (HR, 0.757; 95% CI 0.505-0.945; P = .0137). Patients with greatest benefit from abema-F were exactly the patients who needed the most help – those with visceral metastases (HR 0.675) and with primary resistance to prior hormonal therapy (HR, 0.686).

At 3 years, at least three times as many patients remained progression free with abema-F, compared with placebo-F, and the abema-F patients experienced prolongation in time to eventual chemotherapy (50.2 months vs. 22.1 months; HR, 0.625).

What this means in clinical practice

Many times I find myself sitting at the annual meeting of the American Society of Clinical Oncology and thinking, “Only a medical oncologist like me would find this result exciting.” Prior to ESMO 2019, MONARCH 2 (and a similar study presented at ESMO 2019, MONALEESA-3, which employed an alternative CDK 4/6 inhibitor, ribociclib, with similar OS results) added to the body of literature that caused NCCN guidelines to list all of the approved CDK 4/6 inhibitors plus endocrine therapy for first- or second-line use in patients with hormone-receptor positive, HER2/neu-negative mBC. NCCN guidelines have the caveat that, among patients with disease progression on CDK 4/6 inhibitors in the first-line setting, there are no data to support continuing the CDK 4/6 inhibitor or switching to an alternative CDK 4/6 inhibitor thereafter.

For that shrinking group of patients and doctors who choose to avoid CDK 4/6 inhibitors for first-line treatment, as we describe risks and benefits of using a CDK 4/6 inhibitor for second- or third-line therapy, we have high-quality OS information from ESMO 2019 to answer the “Is it worth it?” question.

Are the results of MONARCH 2 and MONALEESA-3 practice changing? No. We were already convinced. Should we be excited that we have this new information for discussions with our patients? Absolutely.
 

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

BARCELONA – A progressive aerobic and resistance exercise intervention improved the android:gynoid fat ratio (AGFR) in breast cancer survivors, which could provide important health benefits.

AGFR is associated with increased risk for cardiovascular disease and type 2 diabetes in breast cancer survivors, therefore exercise-induced AGFR improvement may reduce the risk for such comorbid conditions, Christina Dieli-Conwright, PhD, of the University of Southern California Norris Comprehensive Cancer Center, Los Angeles, and colleagues reported in a poster at the European Society for Medical Oncology Congress.

A significant decrease in AGFR from baseline was noted in 50 survivors of stage I-III breast cancer who participated in the exercise intervention, compared with 50 such survivors randomized to a usual care group (P less than .001), and strong correlations were found between AGFR and homeostatic model assessment of insulin resistance (HOMA-IR; r = 0.95; P less than .01), the investigators found.

Study participants had a mean age of 53 years, 54% were overweight (body mass index greater than 25 kg/m²), 63% were Hispanic, 90% had undergone a mastectomy, and 76% received chemotherapy and radiation therapy. Adherence to the intervention, which involved three weekly sessions of supervised, progressive, moderate-to-vigorous aerobic and resistance exercise for 16 weeks, was 95%.

AGFR was calculated using whole-body dual-energy x-ray absorptiometry and HOMA-IR was calculated using fasting insulin and glucose levels.

“Exercise reduces fat mass in breast cancer survivors, however, few studies have focused on AGFR,” the investigators wrote.

The findings of the current study suggest that a progressive aerobic and resistance exercise intervention is an effective strategy for decreasing AGFR in breast cancer survivors, they concluded.

The National Cancer Institute funded the study. The authors reported having no disclosures.

SOURCE: Dieli-Conwright C et al. ESMO 2019, Abstract 228P.

BARCELONA – A progressive aerobic and resistance exercise intervention improved the android:gynoid fat ratio (AGFR) in breast cancer survivors, which could provide important health benefits.

AGFR is associated with increased risk for cardiovascular disease and type 2 diabetes in breast cancer survivors, therefore exercise-induced AGFR improvement may reduce the risk for such comorbid conditions, Christina Dieli-Conwright, PhD, of the University of Southern California Norris Comprehensive Cancer Center, Los Angeles, and colleagues reported in a poster at the European Society for Medical Oncology Congress.

A significant decrease in AGFR from baseline was noted in 50 survivors of stage I-III breast cancer who participated in the exercise intervention, compared with 50 such survivors randomized to a usual care group (P less than .001), and strong correlations were found between AGFR and homeostatic model assessment of insulin resistance (HOMA-IR; r = 0.95; P less than .01), the investigators found.

Study participants had a mean age of 53 years, 54% were overweight (body mass index greater than 25 kg/m²), 63% were Hispanic, 90% had undergone a mastectomy, and 76% received chemotherapy and radiation therapy. Adherence to the intervention, which involved three weekly sessions of supervised, progressive, moderate-to-vigorous aerobic and resistance exercise for 16 weeks, was 95%.

AGFR was calculated using whole-body dual-energy x-ray absorptiometry and HOMA-IR was calculated using fasting insulin and glucose levels.

“Exercise reduces fat mass in breast cancer survivors, however, few studies have focused on AGFR,” the investigators wrote.

The findings of the current study suggest that a progressive aerobic and resistance exercise intervention is an effective strategy for decreasing AGFR in breast cancer survivors, they concluded.

The National Cancer Institute funded the study. The authors reported having no disclosures.

SOURCE: Dieli-Conwright C et al. ESMO 2019, Abstract 228P.

BARCELONA – A progressive aerobic and resistance exercise intervention improved the android:gynoid fat ratio (AGFR) in breast cancer survivors, which could provide important health benefits.

AGFR is associated with increased risk for cardiovascular disease and type 2 diabetes in breast cancer survivors, therefore exercise-induced AGFR improvement may reduce the risk for such comorbid conditions, Christina Dieli-Conwright, PhD, of the University of Southern California Norris Comprehensive Cancer Center, Los Angeles, and colleagues reported in a poster at the European Society for Medical Oncology Congress.

A significant decrease in AGFR from baseline was noted in 50 survivors of stage I-III breast cancer who participated in the exercise intervention, compared with 50 such survivors randomized to a usual care group (P less than .001), and strong correlations were found between AGFR and homeostatic model assessment of insulin resistance (HOMA-IR; r = 0.95; P less than .01), the investigators found.

Study participants had a mean age of 53 years, 54% were overweight (body mass index greater than 25 kg/m²), 63% were Hispanic, 90% had undergone a mastectomy, and 76% received chemotherapy and radiation therapy. Adherence to the intervention, which involved three weekly sessions of supervised, progressive, moderate-to-vigorous aerobic and resistance exercise for 16 weeks, was 95%.

AGFR was calculated using whole-body dual-energy x-ray absorptiometry and HOMA-IR was calculated using fasting insulin and glucose levels.

“Exercise reduces fat mass in breast cancer survivors, however, few studies have focused on AGFR,” the investigators wrote.

The findings of the current study suggest that a progressive aerobic and resistance exercise intervention is an effective strategy for decreasing AGFR in breast cancer survivors, they concluded.

The National Cancer Institute funded the study. The authors reported having no disclosures.

SOURCE: Dieli-Conwright C et al. ESMO 2019, Abstract 228P.