Gralow, Julie R.

PURPOSE This guideline updates recommendations of the ASCO guideline on chemotherapy and targeted therapy for patients with human epidermal growth factor receptor 2–negative metastatic breast cancer (MBC) that is either endocrine-pretreated or hormone receptor (HR)–negative. METHODS An Expert Panel conducted a targeted systematic literature review guided by a signals approach to identify new, potentially practice-changing data that might translate into revised guideline recommendations. RESULTS The Expert Panel reviewed abstracts from the literature review and retained 14 articles. RECOMMENDATIONS Patients with triple-negative, programmed cell death ligand-1–positive MBC may be offered the addition of immune checkpoint inhibitor to chemotherapy as first-line therapy. Patients with triple-negative, programmed cell death ligand-1–negative MBC should be offered single-agent chemotherapy rather than combination chemotherapy as first-line treatment, although combination regimens may be offered for life-threatening disease. Patients with triple-negative MBC who have received at least two prior therapies for MBC should be offered treatment with sacituzumab govitecan. Patients with triple-negative MBC with germline BRCA mutations previously treated with chemotherapy may be offered a poly (ADP-ribose) polymerase inhibitor rather than chemotherapy. Patients with HR-positive human epidermal growth factor receptor 2–negative MBC for whom chemotherapy is being considered should be offered single–agent chemotherapy rather than combination chemotherapy, although combination regimens may be offered for highly symptomatic or life-threatening disease. Patients with HR-positive MBC with disease progression on an endocrine agent may be offered treatment with either endocrine therapy with or without targeted therapy or single-agent chemotherapy. Patients with HR-positive MBC with germline BRCA mutations no longer benefiting from endocrine therapy may be offered a poly (ADP-ribose) polymerase inhibitor rather than chemotherapy. No recommendation regarding when a patient's care should be transitioned to hospice or best supportive care alone is possible. Additional information is available at www.asco.org/breast-cancer-guidelines .

Abstract Funding: Supported by National Cancer Institute grants U10CA180888, U10CA180819, U10CA180820, U10CA180821, U10CA180868, U10CA180863; and in part by Susan G. Komen for the Cure® Research Program, The Hope Foundation for Cancer Research, Breast Cancer Research Foundation, and Genomic Health, Inc. Acknowledgement: The authors wish to thank Dr. Ana M. Gonzalez-Angulo, MD, for her invaluable contributions to the design and implementation of this study. Background: The clinical utility of the RS to determine CT benefit is well established in pts with HR+, HER2-, axillary lymph node (LN)-negative BC. Retrospective analyses from SWOG S8814 support the potential prognostic and predictive role of RS for CT benefit in postmenopausal pts with LN+ BC. SWOG S1007 is a prospective, randomized trial of endocrine therapy (ET) vs. chemoendocrine therapy (CET) in women with 1-3 +LN and a RS < 25 (NCT01272037). Methods: Eligibility criteria included women > 18 years of age with HR+, HER2- BC and 1-3 +LN and no contraindications to taxane and/or anthracycline based CT. Women with a RS < 25 were randomized to receive ET or CET in 1:1 randomization using 3 stratification factors: (1) RS (0-13 vs.14-25); (2) menopausal status; and (3) axillary nodal dissection vs. sentinel node biopsy. The primary objective was to determine the effect of CT on invasive disease-free survival (IDFS) and whether the effect depended on the RS. The primary analysis was to test for a significant interaction of the treatment arm and continuous RS using a Cox regression model for IDFS, adjusting for treatment, RS, and menopausal status. A total of 832 IDFS events were expected for the final analysis. Secondary objectives included overall survival (OS). The protocol specified that interaction between treatment and the stratification variables was to be tested and, if significant, separate analyses performed by stratum. Annual interim analyses were planned starting at 24% of events. At the third interim analysis with 410 IDFS events, the Data and Safety Monitoring Committee recommended reporting results, with a decision by the NCI’s Cancer Therapy Evaluation Program, the study sponsor. Results: Of the 9,383 women screened from 2/28/11-9/29/17, 5,083 pts (54.2%) were randomized. With a median follow-up of 5.1 years, 447 IDFS events have been observed. For the primary analysis, the interaction test for CT benefit and continuous RS was not statistically significant, p=0.30. In a model with CT, RS, and menopausal status (no interaction term), higher continuous RS was associated with worse IDFS [HR 1.06, 2-sided p<0.001, 95% Confidence Interval (CI) 1.04-1.07], and CT was associated with an improvement in IDFS (HR 0.81, p=0.026, 95% CI 0.67-0.98). In a pre-specified analysis, a significant interaction was identified between CT and menopausal status (p=0.004), necessitating separate analyses by menopausal status. In postmenopausal pts (N=3350, 67%), adjusting for continuous RS, the HR for CET vs. ET was not significant (HR=0.97, p=0.82, 95% CI 0.78-1.22; 5-year IDFS 91.6% vs. 91.9%) indicating no benefit from CT. In premenopausal pts (N=1665, 33%), the HR (0.54) was statistically significant (p=0.0004, 95% CI 0.38-0.76; 5-year IDFS 94.2% vs. 89.0%), indicating CT benefit. In premenopausal pts, ovarian suppression was performed in 15.9% vs. 3.7% (ET vs. CET), and 47.9% vs. 26.4% reported menstruation after 6 months of treatment. Although the number of events is limited, the HR for treatment adjusted by RS for OS in premenopausal pts was 0.47 (p=0.032, 95% CI 0.24-0.94). At this time, there is no differential effect with CT in regard to other stratification factors. Conclusions: There is a significant differential treatment effect of CT benefit based on RS for premenopausal vs. postmenopausal women requiring separate analyses. While only 54% of the protocol specified events are recorded and pts will be followed for 15 years, the current data show that adjuvant therapy can be de-escalated to ET alone in postmenopausal pts with a RS < 25 and 1-3 +LN. However, there is a strong IDFS benefit for CET in premenopausal pts, with an early indication of an OS improvement. Citation Format: Kevin Kalinsky, William E Barlow, Funda Meric-Bernstam, Julie R Gralow, Kathy S Albain, Daniel Hayes, Nancy Lin, Edith A Perez, Lori J Goldstein, Stephen Chia, Subkhbinder Dhesy-Thind, Priya Rastogi, Emilio Alba, Suzette Delaloge, Miguel Martín, Miguel Gil Gil, Claudia Arce-Salinas, Etienne Brain, In Hae Park, Jean-Yves Pierga, Ana Hernandez Lluch, Manuel Ramos Vasquez, Manuel Ruiz Borrego, Kyung Hae Jung, Jean-Marc Ferrero, Anne Schott, Steve Shak, Priyanka Sharma, Danika L Lew, Jieling Miao, Debu Tripathy, Gabriel Hortobagyi, Lajos Pusztai. First results from a phase III randomized clinical trial of standard adjuvant endocrine therapy (ET) +/- chemotherapy (CT) in patients (pts) with 1-3 positive nodes, hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer (BC) with recurrence score (RS) < 25: SWOG S1007 (RxPonder) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS3-00.

Abstract Background: Evidence from randomized trials, including a recent meta-analysis, suggests that adjuvant bisphosphonates can decrease recurrence and death in postmenopausal women with early-stage breast cancer. Bisphosphonates (BP) have been included as adjuvant therapy for postmenopausal breast cancer patients in multiple guidelines. SWOG S0307 compared efficacy of 3 BPs in early stage breast cancer, with no evidence of differences in efficacy on breast cancer outcomes by type of bisphosphonate, either in the overall analysis or subgroups. BPs are generally well tolerated, with a relatively low risk of serious adverse effects. Treatment for hormone sensitive breast cancer frequently includes treatment with an aromatase inhibitor (AI) or ovarian function suppression (OFS), both of which can accelerate bone loss, decrease bone density, and increase fractures. In addition to decreasing breast cancer events, BPs have been shown to decrease fractures in breast cancer patients receiving AIs or OFS. However, concerns have been raised about the risk of atypical femur fractures (AFF), a rare subtype of fragility fractures, which appear to increase with longer BP use (3-100/100,000 person-years) (Shane 2013). This substudy evaluated all fractures occurring in patients enrolled on S0307. Methods: Patients with stage I-III breast cancer who were receiving adjuvant systemic therapy were randomized to receive 3 years of intravenous zoledronic acid (ZA) 4 mg IV given every 4 weeks for the first six months, and then every 3 months for the following 2.5 years, oral clodronate (CLOD) 1,600 mg/day orally, or oral ibandronate (IBAN) 50 mg/day orally. The primary endpoint was disease-free survival (DFS). On-treatment data collection forms specifically queried whether a fracture had occurred during the reporting period, the site of the fracture, and whether or not it was associated with trauma. Results: A total of 6,097 patients were randomized to S0307, with a median age of 53 years. Rates for overall fractures at 7.7 years were higher for CLOD (9.3%) compared to IBAN (7.4%) and ZA (7.1%) (p=0.02), with differences being mostly in the spine. Traumatic fracture differences were not significant (CLOD 2.0%, ZA 1.9%, IBAN 1.7%; p=0.83). Fragility fracture rates were 5.2% with ZA, 7.2% with CLOD, and 5.6% with IBAN. Ankle fractures were the most common fracture site at 2.8% overall. Leg fractures, including femur fractures, were relatively low with a rate of 1.5% overall and not different between agents. AFF were not specifically queried/determined. Conclusion: In S0307, BPs were used in higher doses than is recommended for treatment of postmenopausal osteoporosis. There is limited data comparing the long-term effects across BP drugs used at these higher doses on the skeleton. In S0307, an overall fracture rate of 8% was seen in early stage breast cancer patients despite receiving BPs along with conventional systemic therapy. Fracture rates were slightly higher for CLOD than ZA and IBAN for fragility and overall fractures, but similar for traumatic fractures. This may reflect the potency of CLOD or the dosing schedule. Rates of femur fractures were relatively low in all arms without evidence of excess femur fractures. Funding: NIH/NCI CA180888, CA180819, CA180820, CA180821, CA180868, CA180863, CA196175; BCRF, Komen, Berlex (Bayer), Roche/Genentech, Novartis. Citation Format: Rachel L (MD) Yung, Jieling Miao, Alexander HG Paterson, Mark Clemons, Elizabeth C Dees, James N Ingle, Carla I Falkson, William Barlow, Gabriel N Hortobagyi, Julie R Gralow. Fractures in women with breast cancer receiving high-dose bisphosphonates to prevent breast cancer metastases as part of the SWOG S0307 trial (ClinicalTrials.gov Identifier: NCT00127205) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-18-02.

Abstract Background Although physical activity has been consistently associated with reduced breast cancer mortality, evidence is largely based on data collected at one occasion. We examined how pre- and postdiagnosis physical activity was associated with survival outcomes in high-risk breast cancer patients. Methods Included were 1340 patients enrolled in the Diet, Exercise, Lifestyle and Cancer Prognosis (DELCaP) Study, a prospective study of lifestyle and prognosis ancillary to a SWOG clinical trial (S0221). Activity before diagnosis, during treatment, and at 1- and 2-year intervals after enrollment was collected. Patients were categorized according to the Physical Activity Guidelines for Americans as meeting the minimum guidelines (yes/no) and incrementally as inactive, low active, moderately active (meeting the guidelines), or high active. Results In joint-exposure analyses, patients meeting the guidelines before and 1 year after diagnosis experienced statistically significant reductions in hazards of recurrence (hazard ratio [HR] = 0.59, 95% confidence interval [CI] = 0.42 to 0.82) and mortality (HR = 0.51, 95% CI = 0.34–0.77); associations were stronger at 2-year follow-up for recurrence (HR = 0.45, 95% CI = 0.31 to 0.65) and mortality (HR = 0.32, 95% CI = 0.19 to 0.52). In time-dependent analyses, factoring in activity from all time points, we observed striking associations with mortality for low- (HR = 0.41, 95% CI = 0.24 to 0.68), moderate- (HR = 0.42, 95% CI = 0.23 to 0.76), and high-active patients (HR = 0.31, 95% CI = 0.18 to 0.53). Conclusions Meeting the minimum guidelines for physical activity both before diagnosis and after treatment appears to be associated with statistically significantly reduced hazards of recurrence and mortality among breast cancer patients. When considering activity from all time points, including during treatment, lower volumes of regular activity were associated with similar overall survival advantages as meeting and exceeding the guidelines.

9515 Background: CC 49907 showed superiority of standard therapy (cyclophosphamide/doxorubicin [AC] or cyclophosphamide/methotrexate/5-fluorouracil [CMF]) over capecitabine[C]. Dose adjustments made for renal insufficiency (RI) for methotrexate and C; ideal body weight used. Purpose was to analyze the relationship between RF at baseline and 5 endpoints: toxicity, dose modification, therapy completion, relapse-free survival [RFS] and overall survival [OS]. Methods: Pre-treatment RF was calculated (Cockcroft-Gault). Endpoints assessed by regimen. RF was tested as a dichotomous and continuous variable of stages 1,2 vs. 3,4 kidney disease (National Kidney Foundation). Logistic regression modeled the relationship between renal stage and the first three endpoints of toxicity, dose modification and therapy completion. Toxicity divided by hematologic or not. The relationship of RFS and OS with RF was assessed with the logrank test and as a continuous variable with Wald chi square. Results: 619 patients; incidence of stage 3/4 RI(<60 ml/min) was: CMF=72%; AC=64%; C=75%. With AC the incidence of toxicity differed by renal function. 31% of patients with poorer function >grade 3 non-hematologic toxicity vs. 14% with better function(p=0.011). There was a suggestion of effect of RF on OS and RFS for C-treated patients. RF was not associated with dose modification, premature therapy termination, RFS or OS for the CMF-treated patients. Conclusions: 1) AC: declining RF was associated with increased non-hematologic toxicity. 2)Patients with RI who received dose modifications were not at increased risk for complications in comparison to those who did not have renal insufficiency and received full dose. 3)Declining RF did not affect therapy completion. 4)C: suggestion that worse RF was related to poorer RFS or OS. 5)Exclusion of patients from clinical trials with RI based on concern of excessive hematologic toxicity may not be justified with appropriate modification. 6)Results should be considered in the design of clinical trials for older patients.

CRA1008 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June, 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.

520 Background: There is considerable interest in developing HER2 testing criteria for adjuvant H. We used the 21-gene assay to examine the relationship of HER2 mRNA to benefit from H. Methods: N9831 compared adjuvant chemotherapy AC-T to concurrent chemotherapy-trastuzumab AC-TH in stage I-III HER2+ breast cancer. Recurrence Score (RS) and HER2 mRNA expression were determined by Oncotype DX (neg<10.7, equiv 10.7 to <11.5, and pos ≥11.5 log2 expression units). Cox regression was used to assess the association of HER2 expression with H benefit for distant recurrence. Results: Median follow-up: 7.4 yrs. Of 1,940 total pts, 901 had consent and sufficient tissue. HER2 by RT-PCR was neg in 130 (14%), equiv in 85 (9%), and pos in 686 (76%) pts. Concordance between HER2 assessments was 95% for RT-PCR vs central IHC (>10% + cells = +), 91% for RT-PCR vs central FISH (≥2.0 = pos) and 94% for central IHC vs central FISH. In the primary analysis, the association of HER2 expression with H benefit was marginally non-significant (P=0.057). In hormone receptor pos pts (local IHC) the association was significant (P=0.002). The association was nonlinear with the greatest estimated benefit at lower and higher HER2 mRNA expression levels. The observed treatment benefit in low HER2 pts was not due to imbalance between arms in RS and individual gene expression values. Conclusions: Concordance among HER2 assessments by central IHC, FISH, and RT-PCR was high. Association of HER2 mRNA expression with H benefit was marginally non-significant. A consistent benefit of trastuzumab irrespective of mHER2 levels was observed in the pts with either IHC+ or FISH+ tumors. Benefit was observed in pts with high HER2 by RT-PCR but also observed for the small groups of pts with negative results by quantitative RT-PCR or FISH (Table). Plausible mechanisms for this observation will be discussed. [Table: see text]

PURPOSE Despite reported widespread use of dietary supplements during cancer treatment, few empirical data with regard to their safety or efficacy exist. Because of concerns that some supplements, particularly antioxidants, could reduce the cytotoxicity of chemotherapy, we conducted a prospective study ancillary to a therapeutic trial to evaluate associations between supplement use and breast cancer outcomes. METHODS Patients with breast cancer randomly assigned to an intergroup metronomic trial of cyclophosphamide, doxorubicin, and paclitaxel were queried on their use of supplements at registration and during treatment (n =1,134). Cox proportional hazards regression adjusting for clinical and lifestyle variables was used. Recurrence and survival were indexed at 6 months after enrollment using a landmark approach. RESULTS There were indications that use of any antioxidant supplement (vitamins A, C, and E; carotenoids; coenzyme Q10) both before and during treatment was associated with an increased hazard of recurrence (adjusted hazard ratio [adjHR], 1.41; 95% CI, 0.98 to 2.04; P = .06) and, to a lesser extent, death (adjHR, 1.40; 95% CI, 0.90 to 2.18; P = .14). Relationships with individual antioxidants were weaker perhaps because of small numbers. For nonantioxidants, vitamin B12 use both before and during chemotherapy was significantly associated with poorer disease-free survival (adjHR, 1.83; 95% CI, 1.15 to 2.92; P < .01) and overall survival (adjHR, 2.04; 95% CI, 1.22 to 3.40; P < .01). Use of iron during chemotherapy was significantly associated with recurrence (adjHR, 1.79; 95% CI, 1.20 to 2.67; P < .01) as was use both before and during treatment (adjHR, 1.91; 95% CI, 0.98 to 3.70; P = .06). Results were similar for overall survival. Multivitamin use was not associated with survival outcomes. CONCLUSION Associations between survival outcomes and use of antioxidant and other dietary supplements both before and during chemotherapy are consistent with recommendations for caution among patients when considering the use of supplements, other than a multivitamin, during chemotherapy.

Abstract Background Adjuvant bisphosphonates, when given in a low-estrogen environment, can decrease breast cancer recurrence and death. Treatment guidelines include recommendations for adjuvant bisphosphonates in postmenopausal patients. SWOG/Alliance/Canadian Cancer Trials Group/ECOG-ACRIN/NRG Oncology study S0307 compared the efficacy of three bisphosphonates in early-stage breast cancer. Methods Patients with stage I–III breast cancer were randomly assigned to 3 years of intravenous zoledronic acid, oral clodronate, or oral ibandronate. The primary endpoint was disease-free survival (DFS) with overall survival as a secondary outcome. All statistical tests were two-sided. Results A total of 6097 patients enrolled. Median age was 52.7 years. Prior to being randomly assigned, 73.2% patients indicated preference for oral vs intravenous formulation. DFS did not differ across arms in a log-rank test (P = .49); 5-year DFS was 88.3% (zoledronic acid: 95% confidence interval [CI] = 86.9% to 89.6%), 87.6% (clodronate: 95% CI = 86.1% to 88.9%), and 87.4% (ibandronate: 95% CI = 85.6% to 88.9%). Additionally, 5-year overall survival did not differ between arms (log rank P = .50) and was 92.6% (zoledronic acid: 95% CI = 91.4% to 93.6%), 92.4% (clodronate: 95% CI = 91.2% to 93.5%), and 92.9% (ibandronate: 95% CI = 91.5% to 94.1%). Bone as first site of recurrence did not differ between arms (P = .93). Analyses based on age and tumor subtypes showed no treatment differences. Grade 3/4 toxicity was 8.8% (zoledronic acid), 8.3% (clodronate), and 10.5% (ibandronate). Osteonecrosis of the jaw was highest for zoledronic acid (1.26%) compared with clodronate (0.36%) and ibandronate (0.77%). Conclusions We found no evidence of differences in efficacy by type of bisphosphonate, either in overall analysis or subgroups. Despite an increased rate of osteonecrosis of the jaw with zoledronic acid, overall toxicity grade differed little across arms. Given that patients expressed preference for oral formulation, efforts to make oral agents available in the United States should be considered.