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Background HER2-overexpressing breast cancer (BC) is common among young patients and poses a public health burden. Adjuvant anti-HER2/neu therapy with trastuzumab reduces the risk of recurrence and improves survival. Methods A web-based survey was sent to 386 physicians of the “TEACH” trial in 2011 to determine access to HER2/neu testing and treatment patterns for HER2-overexpressing BC. Results There were 151 responders (39%) from 28 countries. Ninety-seven percent reported HER2/neu expression is routinely measured in their institutions by immunohistochemistry (85%), FISH (80%) and other methods (16%). Twenty percent of responders from Asia reported that the test was not routinely available. Forty-eight percent of participants reported instances when adjuvant HER2-directed therapy was recommended to a patient who eventually did not receive it. Reasons for not receiving trastuzumab was cost (73%, p < 0.0001) in low- and middle-income countries and co-morbidities in high-income countries (43%, p = 0.003). Conclusions This survey reflects the availability of HER2/neu testing and anti-HER2/neu therapy among physicians who participated in TEACH. A high proportion of women with HER2-overexpressing BC may not receive standard adjuvant therapy due to unavailability of the test and cost of therapy. Despite having some limitations, such as a possible selection bias of participating physicians, variable definitions of access to healthcare among respondents, and changes in trastuzumab availability since 2011, our results demonstrate that access to care and region of practice impact the implementation of cancer treatments. [ABSTRACT FROM AUTHOR]

Sacituzumab govitecan (SG), a novel antibody–drug conjugate (ADC) targeting TROP2, is approved for pre-treated metastatic triple-negative breast cancer (mTNBC). We conducted an investigator-initiated clinical trial evaluating neoadjuvant (NA) SG (NCT04230109), and report primary results. Participants with early-stage TNBC received NA SG for four cycles. The primary objective was to assess pathological complete response (pCR) rate in breast and lymph nodes (ypT0/isN0) to SG. Secondary objectives included overall response rate (ORR), safety, event-free survival (EFS), and predictive biomarkers. A response-guided approach was utilized, and subsequent systemic therapy decisions were at the discretion of the treating physician. From July 2020 to August 2021, 50 participants were enrolled (median age = 48.5 years; 13 clinical stage I disease, 26 stage II, 11 stage III). Forty-nine (98%) completed four cycles of SG. Overall, the pCR rate with SG alone was 30% [ n = 15, 95% confidence interval (CI) 18% to 45%]. The ORR per RECIST V1.1 after SG alone was 64% (n = 32/50, 95% CI 77% to 98%). Higher Ki-67 and tumor-infiltrating lymphocytes (TILs) were predictive of pCR to SG (P = 0.007 for Ki-67 and 0.002 for TILs), while baseline TROP2 expression was not (P = 0.440). Common adverse events were nausea (82%), fatigue (76%), alopecia (76%), neutropenia (44%), and rash (48%). With a median follow-up time of 18.9 months (95% CI 16.3-21.9 months), the 2-year EFS for all participants was 95%. Among participants with a pCR with SG (n = 15), the 2-year EFS was 100%. In the first NA trial with an ADC in localized TNBC, SG demonstrated single-agent efficacy and feasibility of response-guided escalation/de-escalation. Further research on optimal duration of SG as well as NA combination strategies, including immunotherapy, are needed. • NA treatment with SG for localized TNBC is safe and feasible. • Approximately two-thirds of patients responded to NA SG alone, and 30% achieved pCR without additional chemotherapy. • Higher Ki-67 and TILs were predictive of pCR to SG, whereas TROP2 expression was not. [ABSTRACT FROM AUTHOR]

Background Previous data suggest that the immune microenvironment plays a critical role in human epidermal growth factor receptor 2 (HER2) -positive breast cancer; however, there is little known about the immune profiles of small HER2-positive tumors. In this study, we aimed to characterize the immune microenvironment of small HER2-positive breast cancers included in the Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer (APT) trial and to correlate the immune markers with pathological and molecular tumor characteristics. Patients and methods The APT trial was a multicenter, single-arm, phase II study of paclitaxel and trastuzumab in patients with node-negative HER2-positive breast cancer. The study included 406 patients with HER2-positive, node-negative breast cancer, measuring up to 3 cm. Exploratory analysis of tumor infiltrating lymphocytes (TIL), programmed death-ligand 1 (PD-L1) expression (by immunohistochemistry), and immune gene signatures using data generated by nCounter PanCancer Pathways Panel (NanoString Technologies, Seattle, WA), and their association with pathological and molecular characteristics was carried out. Results Of the 406 patients, 328 (81%) had at least one immune assay carried out: 284 cases were evaluated for TIL, 266 for PD-L1, and 213 for immune gene signatures. High TIL (≥60%) were seen with greater frequency in hormone-receptor (HR) negative, histological grades 2 and 3, as well in HER2-enriched and basal-like tumors. Lower stromal PD-L1 (≤1%) expression was seen with greater frequency in HR-positive, histological grade 1, and in luminal tumors. Both TIL and stromal PD-L1 were positively correlated with 10 immune cell signatures, including Th1 and B cell signatures. Luminal B tumors were negatively correlated with those signatures. Significant correlation was seen among these immune markers; however, the magnitude of correlation did not indicate a monotonic relationship between them. Conclusion Immune profiles of small HER2-positive breast cancers differ according to HR status, histological grade, and molecular subtype. Further work is needed to explore the implication of these findings on disease outcome. Clinical trial registration clinicaltrials.gov identifier: NCT00542451. [ABSTRACT FROM AUTHOR]

Background We report longitudinal health-related quality-of-life (HRQoL) data from the international, randomized, double-blind, placebo-controlled phase III ExteNET study, which demonstrated an invasive disease-free survival benefit of extended adjuvant therapy with neratinib over placebo in human epidermal growth factor receptor-2-positive early-stage breast cancer. Patients and methods Women (N   =   2840) with early-stage HER2-positive breast cancer who had completed trastuzumab-based adjuvant therapy were randomly assigned to neratinib 240  mg/day or placebo for 12  months. HRQoL was an exploratory end point. Patients completed the Functional Assessment of Cancer Therapy–Breast (FACT-B) and EuroQol 5-Dimensions (EQ-5D) questionnaires at baseline and months 1, 3, 6, 9, and 12. Changes from baseline were compared using analysis of covariance with no imputation for missing values. Sensitivity analyses used alternative methods. Changes in HRQoL scores were regarded as clinically meaningful if they exceeded previously reported important differences (IDs). Results Of the 2840 patients (intention-to-treat population), 2407 patients were evaluable for FACT-B (neratinib, N   =   1171; placebo, N   =   1236) and 2427 patients for EQ-5D (neratinib, N   =   1186; placebo, N   =   1241). Questionnaire completion rates exceeded 85%. Neratinib was associated with a decrease in global HRQoL scores at month 1 compared with placebo (adjusted mean differences: FACT-B total, –2.9 points; EQ-5D index, −0.02), after which between-group differences diminished at later time-points. Except for the FACT-B physical well-being (PWB) subscale at month 1; all between-group differences were less than reported IDs. The FACT-B breast cancer-specific subscale showed small improvements with neratinib at months 3–9, but all were less than IDs. Sensitivity analyses exploring missing data did not change the results. Conclusions Extended adjuvant neratinib was associated with a transient, reversible decrease in HRQoL during the first month of treatment, possibly linked to treatment-related diarrhea. With the exception of the PWB subscale at month 1, all neratinib-related HRQoL changes did not reach clinically meaningful thresholds. ClinicalTrials.gov: NCT00878709. [ABSTRACT FROM AUTHOR]

Residual disease after neoadjuvant therapy (NAT) is associated with higher risk of recurrence, including local failure (25%) in triple negative breast cancer (TNBC). Novel combinations that increase the efficacy of standard-of-care treatments on locoregional control are warranted. PARP inhibitors (PARPi) target the DNA damage repair pathway, which is often altered in TNBC, and show promise as radiosensitizers. The objective of this phase I trial (NCT03945721) was to determine the maximum tolerated dose (MTD) of a PARPi, niraparib, in pts with high risk TNBC receiving postoperative radiotherapy (RT). Eligible pts had stage I-III TNBC with residual invasive disease following NAT or primary tumor ≥1 cm after upfront surgery. A 3+3 escalation design was used to test 2 dose levels of QD niraparib (100mg, 200mg) with concurrent RT to the chest wall or breast +/- regional lymph nodes over 4-6 weeks. Dose expansion followed at the MTD. A boost was delivered in pts who had lumpectomy. 2 pts received proton beam RT. Bolus was administered in postmastectomy RT or in cases of dermal lymphatic invasion. Circulating tumor DNA (ctDNA) was collected at baseline, mid-RT, end of RT, and 30 days post-RT to assess the kinetics of ctDNA levels during RT and the association with clinical outcomes. Adverse events (AEs) were assessed using CTCAE v5.0. 21 pts were enrolled from July 2019 – October 2021. The median age was 49 (31-69). 19/21 pts had residual disease after NAT (6 RCB I, 7 RCB II, 6 RCB III); among them, 2 underwent adjuvant chemotherapy prior to enrolling. The remaining 2/21 pts (pT2N0; pT1cN0) received upfront breast conserving surgery followed by adjuvant chemotherapy. In dose escalation, 6 pts received 100mg niraparib + RT and 2 pts received 200mg niraparib + RT. One DLT in the 100mg cohort (G3 dermatitis) was attributed to RT. Two DLTs in the 200mg cohort (G3 thrombocytopenia) were attributed to niraparib and study drug was discontinued. In dose expansion, 13 pts received 100mg niraparib + RT. G3 AEs were dermatitis (4/21), hematologic (4/21), consisting of thrombocytopenia, anemia & lymphopenia, and elevated alkaline phosphatase (1/21). There was one G4 thrombocytopenia. All skin AEs were attributed to RT and were not exacerbated by niraparib. No pts in dose expansion discontinued treatment due to toxicity. 20/21 went on to standard-of-care capecitabine after completing RT. Results of ctDNA will be reported at the meeting. The MTD of niraparib + postop RT was determined to be 100mg QD and was associated with a 24% rate of G3-4 hematologic toxicities and 19% rate of G3 radiation dermatitis in pts with localized TNBC, which is within upper limits of normal for pts in whom chest wall/skin is targeted. These results will be informative for a future larger study testing the efficacy of niraparib + postop RT in high risk TNBC. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): Leptomeningeal disease (LMD) is a devastating diagnosis with limited treatment options and poor prognosis. With recent advances in treatment, women with breast cancer (BC) are living longer and the incidence of LMD in this population is increasing. There remains little data regarding the prognosis and optimal treatment of these patients. As such, we conducted a multi-institutional retrospective review of women with BC LMD and analyzed outcomes based on prognostic factors and treatments.Materials/methods: We analyzed the records of women diagnosed with BC LMD via MRIs of their brain and/or spine between 2000 and 2020 at two academic medical centers. Demographic and clinical characteristics were abstracted from electronic medical records and an in-depth radiographic review was performed by a neuro-radiologist for each case. Univariate and multivariate Cox proportional-hazards models were generated to identify factors associated with prolonged survival. Collection and analysis of the data was approved by institutional IRB.Results: We identified 227 women with BC LMD. Prior to developing LMD, most women initially presented with Stage I-III BC (62.1%) with ductal histology (67.0%) and biological subtypes including ER-positive/HER2-negative (56.8%), HER2-positive (17.6%), and triple-negative (22.0%). LMD was first diagnosed a median of 4.6 years (range: 0 to 34.1 years) after the initial diagnosis of BC, and the median age at LMD diagnosis was 54.6 years (range: 29.4 to 84.5 years). At time of LMD diagnosis, 146 (64.3%) women presented with a Karnofsky Performance Status (KPS) ≥ 70, 90 (39.6%) had a preceding parenchymal brain metastasis, and 23 (10.1%) had LMD as their only site of metastatic disease. Radiographically, classical LMD (61.7%) was observed more frequently than nodular-only LMD (13.2%). Brain-only LMD was present in 55.1% of patients, spine-only in 6.1% of patients, and both brain and spine in 38.8% of patients. Median survival from the time of LMD diagnosis was 4.5 months (95% CI: 3.4-7.8). Pre-treatment clinical factors associated with improved survival on univariate analysis included ER-positive/HER2-negative subtype (P = 0.010), KPS ≥ 70 (P < 0.001), LMD as the only site of metastasis (P = 0.004), stable or controlled extracranial metastases (P = 0.042), absence of leukopenia (P = 0.040) and the presence of nodular LMD (P < 0.001). After adjusting for these clinical factors, the receipt of radiation therapy (adjusted hazard ratio [AHR] 0.50, 95% CI: 0.37 - 0.68), systemic therapy (AHR 0.27, 95% CI: 0.19 - 0.38) and intrathecal chemotherapy (AHR 0.49, 95% CI: 0.33 - 0.75) were all associated with improved survival.Conclusion: In one of the largest multi-institutional reviews to date, we found that several pre-treatment clinical factors were significantly associated with improved survival among women with breast cancer LMD. However, despite treatment overall survival remains poor, and there is a need for new, effective therapies.Author Disclosure: M.G. Milligan: None. A. Aitelli: None. W.A. Mehan: Consultant; Kura Oncology. D.D. Shi: None. D.N. Cagney: Research Grant; Viewray, NhTheraguix. K.S. Oh: None. N. Wang: None. P. Brastianos: Research Grant; Merck, Eli Lily, BMS. Honoraria; Merck, Genentech. Consultant; Angiochem, Dantari Pharmaceuticals, Elevatebio, Eli Lily, Genentech, Pfizer, SK Life Sciences, Tesaro. B. Moy: Research Grant; PUMA biotechnology. N.U. Lin: Research Grant; Genentech, Merck, Pfizer, Seattle Genetics. Consultant; PUMA Biotechnology, Seattle Genetics, Daiichi Sankyo, Astra Zeneca, Denali Therapeutics, California Institute for Regenerative Medicine, Prelude Therapeutics. H.A. Shih: Employee; Dartmouth Hitchcock. Research Grant; AbbVie, NIH. Honoraria; UpToDate. Consultant; Cleveland Clinic. Speaker's Bureau; prIME Oncology. advisory; The Radiosurgery Society. director of clinical operations; Massachusetts General Hospital. clinical operational leader; Massachusetts General Hospital. [ABSTRACT FROM AUTHOR]

CNS metastases is a devastating complication of breast cancer, occurring in approximately 10%–15% of patients with metastatic breast cancer (MBC) and resulting in median survival of less than one year in historic cohorts. Biological factors that govern metastases to the brain, including the role of activating PIK3CA mutations, the most common actionable alterations in HR+/HER2- MBC, are poorly understood. In this retrospective cohort study, we determined the cumulative incidence of brain metastasis in PIK3CA mutant and PIK3CA non-mutant HR+/HER2- MBC patients treated at the Massachusetts General Hospital and genotyped during their routine clinical care with a highly sensitive multiplexed assay for real time mutation profiling of clinical samples. In the overall cohort of 307 patients, 120 patients (39.1%) had PIK3CA mutant disease and 187 patients (60.9%) had PIK3CA non-mutant disease, comparable to previously published results. Median OS from the time of diagnosis of metastatic disease was 3.96 yrs (95% CI 3.40-4.87 yrs) for PIK3CA mutant patients and 4.43 yrs (95% CI 3.82-5.32 yrs) for PIK3CA non-mutant patients, p = 0.6. 22.44% of patients with HR+/HER2- disease developed brain metastases; 30.83% of PIK3CA mutant patients and 17.11% of PIK3CA non-mutant patients developed CNS metastases, p = 0.0049. Median time to the development of CNS disease was 8.61 yrs for PIK3CA mutant subset and not reached (NR) for PIK3CA non-mutant subset, p = 0.0086. Among patients with CNS metastases, median OS for PIK3CA mutant patients was 0.48 yrs (95% CI 0.27-0.74) and for PIK3CA non-mutant it was 1.09 yrs (95% CI 0.39-2.27), p = 0.019). Brain metastases are common in HR+/HER2- MBC. This incidence of brain metastases is particularly high among patients with HR+/HER2- tumors harboring a PIK3CA mutation, where it approaches the incidence historically seen in HER2+ MBC. Early recognition of symptoms potentially related to brain metastases is important even in HR+/HER2- subtype of breast cancer. High incidence of brain metastases in PIK3CA mutant HR+/HER2- MBC warrants development of blood-brain barrier penetrant agents targeting the PI3K/AKT/mTOR pathway. The authors. Has not received any funding. S. Isakoff: Advisory / Consultancy, Research grant / Funding (institution): Myriad; Advisory / Consultancy, Research grant / Funding (institution): Puma; Advisory / Consultancy, Research grant / Funding (institution): Immunomedics; Advisory / Consultancy, Research grant / Funding (institution): Mylan; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): Pharmamar; Advisory / Consultancy, Research grant / Funding (institution): Abbvie; Advisory / Consultancy, Research grant / Funding (institution): OncoPep; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca. A. Bardia: Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution): Immunomedics; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Radius Health; Advisory / Consultancy, Research grant / Funding (institution): Specturm; Advisory / Consultancy, Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Mersana; Research grant / Funding (institution): Innocrin; Research grant / Funding (self): Biothernostics. P.K. Brastianos: Research grant / Funding (institution): Merck; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Bristol-Myer Squibb; Advisory / Consultancy: Genentech-Roche; Advisory / Consultancy: Merck; Advisory / Consultancy: Lily; Advisory / Consultancy: TESARO; Advisory / Consultancy: AngioChem. D. Juric: Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): EMD Serono; Advisory / Consultancy, Research grant / Funding (institution): Syros; Advisory / Consultancy: Ipsen; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Placon Therapeutics. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]