IntroductionMost breast cancers that occur in women with germline BRCA1 mutations are estrogen receptor-negative (ER-) and also typically lack expression of progesterone receptor (PR) and HER2 overexpression. We undertook a study to assess the clinical factors that predict for an estrogen receptor positive (ER+) breast cancer in BRCA1 mutation carriers and to characterize the pathologic features of these tumors.MethodsClinical characteristics of BRCA1 carriers with 58 ER+ and 114 ER- first invasive breast cancers were compared. Pathologic features of BRCA1 ER+ cancers were compared to those of BRCA1 ER- cancers and to age-matched ER+ sporadic cancers.ResultsBRCA1 carriers aged ≥ 50 at diagnosis of first invasive breast cancer were more likely to have an ER+ cancer compared to those aged < 50 (57% vs 29%, P = 0.005). ER+ BRCA1 cancers were less likely than ER- BRCA1 cancers to have "BRCA-associated" features such as high mitotic activity, geographic necrosis/fibrotic focus, and pushing margins (RR 0.06, 0.22, 0.24; P < 0.001, 0.02, 0.03 respectively). When compared to sporadic ER+ cancers, ER+ BRCA1 cancers were more often of invasive ductal type (RR 2.4, P = 0.03), with a high mitotic rate (RR 5.0, P = 0.006) and absent or mild lymphocytic infiltrate (RR 10.2, P = 0.04).ConclusionsBRCA1 carriers who are older at first breast cancer diagnosis are more likely to have ER+ tumors than younger BRCA1 carriers. These ER+ cancers appear pathologically "intermediate" between ER- BRCA1 cancers and ER+ sporadic breast cancers raising the possibility that either some ER+ BRCA1 cancers are incidental or that there is a unique mechanism by which these cancers develop.

PURPOSE The aim of this work is to update key recommendations of the ASCO guideline adaptation of the Cancer Care Ontario guideline on the selection of optimal adjuvant chemotherapy regimens for early breast cancer and adjuvant targeted therapy for breast cancer. 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 identified one article for inclusion that reported results of the phase III, open-label KATHERINE trial. In the KATHERINE trial, patients with stage I to III human epidermal growth factor receptor 2 (HER2)–positive breast cancer with residual invasive disease in the breast or axilla after completing neoadjuvant chemotherapy and HER2-targeted therapy were allocated to adjuvant trastuzumab emtansine (T-DM1; n = 743) or to trastuzumab (n = 743). Invasive disease–free survival was significantly higher in the T-DM1 group than in the trastuzumab arm (hazard ratio, 0.50; 95% CI, 0.39 to 0.64; P < .001), and risk of distant recurrence was lower in patients who received T-DM1 than in patients who received trastuzumab (hazard ratio, 0.60; 95% CI, 0.45 to 0.79). Grade 3 or higher adverse events occurred in 190 patients (25.7%) who received T-DM1 and in 111 patients (15.4%) who received trastuzumab. RECOMMENDATIONS Patients with HER2-positive breast cancer with pathologic invasive residual disease at surgery after standard preoperative chemotherapy and HER2-targeted therapy should be offered 14 cycles of adjuvant T-DM1, unless there is disease recurrence or unmanageable toxicity. Clinicians may offer any of the available and approved formulations of trastuzumab, including trastuzumab, trastuzumab and hyaluronidase-oysk, and available biosimilars. Additional information can be found at www.asco.org/breast-cancer-guidelines

BACKGROUND Women with BRCA1 mutations develop breast cancer with similar pathologic features to sporadic triple negative (TN) breast cancer, a subtype associated with early disease relapse and poor outcome. We compared the clinical outcome of women with and without BRCA1 mutations who had TN breast cancer treated with conventional chemotherapy. METHODS Women with stage I-III TN breast cancer who had BRCA1 testing within 36 months of diagnosis and received alkylating chemotherapy were identified from clinical databases and a SPORE specimen bank. BRCA2 mutation carriers were excluded, resulting in a study cohort of 46 BRCA1 carriers and 71 non-carriers. Sites of metastasis, relapse rates and survival were compared among carriers and non-carriers. The median follow-up was 75 months. RESULTS BRCA1 carriers were younger at diagnosis (p<0.001) and had smaller tumors (p=0.03) than non-carriers. Freedom from distant metastasis at 5 years was 76% for carriers and 70% for non-carriers (HR 0.79, p=0.5). Sites of distant recurrence did not differ significantly (p=0.15), although BRCA1 carriers had a propensity for brain relapse (58% vs. 24%, p=0.06). Overall survival at 5 years was 82% for carriers and 74% for non-carriers (HR 0.64, p=0.25). Adjusting for age and stage, BRCA1 mutation status was not an independent predictor of survival (HR 0.73, p=0.48). CONCLUSION BRCA1 mutation carriers with TN disease have similar survival rates to non-carriers when treated with alkylating chemotherapy. Women with BRCA1-related breast cancer may benefit from novel therapies that target DNA repair, and further study is needed to identify sporadic TN breast cancers with a BRCA-deficient phenotype.

Mutations in the IDH1 and IDH2 (isocitrate dehydrogenase) genes have been discovered across a range of solid-organ and hematologic malignancies, including acute myeloid leukemia, glioma, chondrosarcoma, and cholangiocarcinoma. An intriguing aspect of IDH-mutant tumors is the aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which may play a pivotal oncogenic role in these malignancies. We describe the first reported case of an IDH1 p.R132L mutation in a patient with hormone receptor-positive (HR1) breast adenocarcinoma. This patient was initially treated for locally advanced disease, but then suffered a relapse and metastasis, at which point an IDH1-R132 mutation was discovered in an affected lymph node. The mutation was subsequently found in the primary tumor tissue and all metastatic sites, but not in an uninvolved lymph node. In addition, the patient's serum and urine displayed marked elevations in the concentration of 2-HG, significantly higher than that measured in six other patients with metastatic HR1 breast carcinoma whose tumors were found to harbor wild-type IDH1. In summary, IDH1 mutations may impact a rare subgroup of patients with breast adenocarcinoma. This may suggest future avenues for disease monitoring through noninvasive measurement of 2-HG, as well as for the development and study of targeted therapies against the aberrant IDH1 enzyme. The Oncologist 2014; 19:602-607 Implications for Practice: Isocitrate dehydrogenase (IDH) mutations have been identified in various hematologic and solid-tumor malignancies. To date, there are no published reports of these mutations in breast cancer. With this article, we describe a case of hormone receptor-positive adenocarcinoma of the breast with an IDH1 (p.R132L) mutation. The impacted patient had markedly elevated levels of serum and urine 2-hydroxyglutarate, an oncometabolite that accumulates as a result of the neomorphic activity of the altered IDH enzyme. IDH1 mutations may impact a rare subgroup of patients with breast adenocarcinoma, and these findings may carry future therapeutic implications, given the emergence of targeted therapies against the altered IDH protein.

Pertuzumab-based regimens, including THP, resulted in higher pCR rates as compared to ddAC-TH, with the THP regimen associated with the best tolerability among patients with localized HER2+ breast cancer. Given the various neoadjuvant regimens, additional studies are needed to determine optimal treatment sequencing and escalation/de-escalation strategies to personalize neoadjuvant regimens for localized HER2+ breast cancer.

512 Background: Sacituzumab govitecan (SG), a novel antibody-drug conjugate in which the topoisomerase 1 inhibitor SN-38 (active metabolite of irinotecan) is linked to a humanized monoclonal antibody targeting the tumor antigen Trop2, is currently approved for treatment of patients (pts) with pre-treated metastatic triple negative breast cancer (TNBC). We conducted a phase 2 study evaluating neoadjuvant (NA) SG as upfront therapy for pts with localized TNBC (NCT04230109). The primary objective was to assess pathological complete response (pCR) rate in breast and lymph nodes (ypT0/isN0) with SG. Secondary objectives included assessment of radiological response rate, evaluation of the safety and tolerability (CTCAE v5.0) and event-free survival (EFS). Methods: Patients with localized TNBC (tumor size ≥1cm, or any size if node positive) with no prior treatment were eligible. SG was administered IV on Days 1, 8 of each 21-day cycle at a starting dose of 10 mg/kg for 4 cycles. After 4 cycles, patients with biopsy-proven residual disease, considered as no pCR for primary endpoint, had the option to receive additional NA therapy at the discretion of the treating physician. Radiologic response (US or MRI) was defined by RECIST version 1.1 using a composite response of CR & PR. Standard descriptive statistics were utilized, including 95% binomial confidence intervals for all rates estimated. Results: From 7/14/20 – 8/31/21, 50 pts were enrolled (median age = 48.5; 11 stage I disease, 24 stage II, 11 stage III, 4 unknown; 62% node negative). The majority (98%; n = 49) of pts completed 4 cycles of SG. Overall, the radiological response rate with SG alone was 62% (n = 31, 95% CI 48%, 77%). 26 pts proceeded directly to surgery after SG. Overall, the pCR rate with SG alone was 30% (n = 15/50, 95% CI 18%, 45%). The other 11 pts had RCB-1 (n = 3), RCB-2 (n = 5), and RCB-3 (n = 3) disease, respectively. Of the 24 pts who received additional NA therapy, 6 had a pCR (3 received anthracycline-based regimen, 2 carboplatin/taxane, and 1 docetaxel/cyclophosphamide). Among pts with a germline BRCA mutation (n = 8), 7 proceeded directly to surgery after SG and 6 had a pCR (86%, 95% CI 42%, 99%). The most common AEs with SG were nausea (82%, n = 41), fatigue (78%, n = 39), alopecia (76%, n = 38), neutropenia (58%, n = 29), anemia (36%, n = 18), and rash (48%, n = 24). 6% of pts required dose-reduction. No pts discontinued SG therapy due to disease progression or AEs; 1 discontinued due to minimal response per investigator preference. At the time of data cut-off (1/18/22), no pts experienced disease recurrence. Updated biomarker and EFS results will be presented at the meeting. Conclusions: In the first neoadjuvant trial in TNBC with an ADC, SG demonstrated single agent efficacy in localized TNBC. Further research on optimal duration of SG as well as NA combination strategies, including immunotherapy, are needed. Clinical trial information: NCT04230109.

There are over 3.5 million breast cancer survivors living in the United States. Key elements of breast cancer survivorship care include monitoring for disease recurrence, addressing medical and psychosocial consequences of treatment, and educating about lifestyle interventions which decrease risk of recurrence, improve quality of life, and improve outcome. We have developed the PAVING the Path to Wellness Program for Breast Cancer Survivors in order to provide education on evidence-based topics from lifestyle medicine, with the goal to help women adopt healthy habits and improve well-being after cancer treatment. The 12-week program includes all 6 pillars of lifestyle medicine, as well as positive psychology, gratitude, and goal setting work. The PAVING the Path to Wellness Program for Breast Cancer Survivors empowers breast cancer survivors with knowledge regarding evidence-based lifestyle recommendations and helps them achieve an improved sense of well-being following treatment. On completion of the program, participants specifically reported an improvement in attitude and well-being. Next steps involve developing a strategy to offer this program to a larger group of cancer survivors.

Breast cancer is the most common female cancer diagnosis in the United States (excluding skin cancers), and the second leading cause of female cancer death. This article highlights the role that lifestyle plays in primary breast cancer prevention, breast cancer treatment, and tertiary breast cancer prevention. Current data regarding the benefits of a predominantly plant-based diet in combination with physical activity and maintenance of a healthy body weight will be reviewed. The evidenced-based patient-focused recommendations developed by the World Cancer Research Fund/American Institute for Cancer Research will be discussed in the context of an overall lifestyle strategy. It is our hope that this publication empowers clinicians to provide patients with personalized cancer-protective lifestyle prescriptions.