PURPOSE To update recommendations on appropriate use of breast cancer biomarker assay results to guide adjuvant endocrine and chemotherapy decisions in early-stage breast cancer. METHODS An updated literature search identified randomized clinical trials and prospective-retrospective studies published from January 2016 to October 2021. Outcomes of interest included overall survival and disease-free or recurrence-free survival. Expert Panel members used informal consensus to develop evidence-based recommendations. RESULTS The search identified 24 studies informing the evidence base. RECOMMENDATIONS Clinicians may use Onco type DX, MammaPrint, Breast Cancer Index (BCI), and EndoPredict to guide adjuvant endocrine and chemotherapy in patients who are postmenopausal or age > 50 years with early-stage estrogen receptor (ER)–positive, human epidermal growth factor receptor 2 (HER2)–negative (ER+ and HER2–) breast cancer that is node-negative or with 1-3 positive nodes. Prosigna and BCI may be used in postmenopausal patients with node-negative ER+ and HER2– breast cancer. In premenopausal patients, clinicians may use Onco type in patients with node-negative ER+ and HER2– breast cancer. Current data suggest that premenopausal patients with 1-3 positive nodes benefit from chemotherapy regardless of genomic assay result. There are no data on use of genomic tests to guide adjuvant chemotherapy in patients with ≥ 4 positive nodes. Ki67 combined with other parameters or immunohistochemistry 4 score may be used in postmenopausal patients without access to genomic tests to guide adjuvant therapy decisions. BCI may be offered to patients with 0-3 positive nodes who received 5 years of endocrine therapy without evidence of recurrence to guide decisions about extended endocrine therapy. None of the assays are recommended for treatment guidance in individuals with HER2-positive or triple-negative breast cancer. Treatment decisions should also consider disease stage, comorbidities, and patient preferences. Additional information is available at www.asco.org/breast-cancer-guidelines .

PURPOSE Talazoparib has demonstrated efficacy in patients with BRCA-positive metastatic breast cancer. This study evaluated the pathologic response of talazoparib alone for 6 months in patients with a known germline BRCA pathogenic variant (g BRCA-positive) and operable breast cancer. METHODS Eligibility included 1 cm or larger invasive tumor and g BRCA-positive disease. Human epidermal growth factor receptor 2–positive tumors were excluded. Twenty patients underwent a pretreatment biopsy, 6 months of once per day oral talazoparib (1 mg), followed by definitive surgery. Patients received adjuvant therapy at physician’s discretion. The primary end point was residual cancer burden (RCB). With 20 patients, the RCB-0 plus RCB-I response rate can be estimated with a 95% CI with half width less than 20%. RESULTS Twenty patients were enrolled from August 2016 to September 2017. Median age was 38 years (range, 23 to 58 years); 16 patients were g BRCA1 positive and 4 patients were g BRCA2 positive. Fifteen patients had triple-negative breast cancer (estrogen receptor/progesterone receptor < 10%), and five had hormone receptor-positive disease. Five patients had clinical stage I disease, 12 had stage II, and three had stage III, including one patient with inflammatory breast carcinoma and one with metaplastic chondrosarcomatous carcinoma. One patient chose to receive chemotherapy before surgery and was not included in RCB analyses. RCB-0 (pathologic complete response) rate was 53% and RCB-0/I was 63%. Eight patients (40%) had grade 3 anemia and required a transfusion, three patients had grade 3 neutropenia, and 1 patient had grade 4 thrombocytopenia. Common grade 1 or 2 toxicities were nausea, fatigue, neutropenia, alopecia, dizziness, and dyspnea. Toxicities were managed by dose reduction and transfusions. Nine patients required dose reduction. CONCLUSION Neoadjuvant single-agent oral talazoparib once per day for 6 months without chemotherapy produced substantial RCB-0 rate with manageable toxicity. The substantive pathologic response to single-agent talazoparib supports the larger, ongoing neoadjuvant trial (ClinicalTrials.gov identifier: NCT03499353 ).

Background: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to a potent topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. Preliminary results from the phase 1 TROPION-PanTumor01 study demonstrate that Dato-DXd has encouraging antitumor activity and a manageable safety profile in patients with non-small cell lung cancer (NSCLC) (Meric-Bernstam, ASCO 2021) and those with triple-negative breast cancer (TNBC) (Bardia, ESMO BC 2021). Updated results from the TNBC cohort are presented here. Methods: TROPION-PanTumor01 (NCT03401385) is a phase 1, multi-center, open-label, 2-part study evaluating Dato-DXd in previously treated patients with solid tumors. Based on the dose-escalation results in patients with NSCLC, Dato-DXd 6 mg/kg intravenously every 3 weeks is being evaluated in patients with advanced/metastatic TNBC and HR+/HER2− breast cancer who relapsed/progressed on standard therapies. Two patients with TNBC received Dato-DXd 8 mg/kg prior to selection of 6 mg/kg for dose expansion. Safety and efficacy were assessed, including objective response rate (ORR) per RECIST version 1.1 by blinded independent central review (BICR). Results: As of the April 6, 2021, data cutoff, 43 patients with TNBC had received ≥1 dose of Dato-DXd, with 27 patients (63%) continuing and 16 patients (37%) discontinuing treatment all due to disease progression. The median age was 53 years (range, 32-82 years). Forty-one patients (95%) had received ≥2 prior lines of therapy; 19 patients (44%) had received prior immunotherapy and 7 (16%) had received prior sacituzumab govitecan. The median duration of treatment was 2.8 months (range, 0.7-6.9 months). The median follow-up was 3.9 months (range, 0.3-9.2 months). Among 38 patients evaluable for response, the ORR by BICR was 39% (15 partial responses [PR]), with 12 confirmed and 3 pending confirmation. The disease control rate was 84% (32/38). The median time to response was 1.35 months (1.2-3.2 months) for the 12 confirmed PRs. All-cause treatment-emergent adverse events (TEAEs; any grade, grade ≥3) were observed in 95% and 35% of patients, respectively; 2 events were grade 4 and 0 grade 5. The most common TEAEs (any grade [≥30%], grade ≥3) included nausea (58%, 0%), stomatitis (53%, 9%), alopecia (35%, N/A), vomiting (35%, 2%), and fatigue (33%, 7%). One patient had grade 3 decreased neutrophil count; no cases of grade ≥3 diarrhea were observed. No cases of treatment-related interstitial lung disease as adjudicated by an independent committee were reported. Serious TEAEs were observed in 5 patients (12%); no TEAEs were associated with death. Dose reductions occurred in 9 patients due to stomatitis, fatigue, mucosal inflammation, dry eye, retinal exudates, and blurred vision (multiple counts per TEAE). Three patients had dose interruptions due to stomatitis, mucosal inflammation, bronchitis, and musculoskeletal chest pain. No patients discontinued treatment due to adverse events. Conclusions: Preliminary results showed that Dato-DXd demonstrates promising antitumor activity with a manageable safety profile in patients with previously treated advanced/metastatic TNBC; confirmatory studies in patients with breast cancer are warranted. Citation Format: Ian Krop, Dejan Juric, Toshio Shimizu, Anthony Tolcher, Alexander Spira, Toru Mukohara, Aaron E. Lisberg, Takahiro Kogawa, Kyriakos P. Papadopoulos, Erika Hamilton, Senthil Damodaran, Jonathan Greenberg, Wen Gu, Fumiaki Kobayashi, Ferdinand Guevara, Takahiro Jikoh, Yui Kawasaki, Funda Meric-Bernstam, Aditya Bardia. Datopotamab deruxtecan in advanced/metastatic HER2- breast cancer: Results from the phase 1 TROPION-PanTumor01 study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS1-05.

Purpose: We sought to determine the significant genomic alterations in patients with metastatic breast cancer (MBC), and survival outcomes in common genotypes. Patients and Methods: High-depth next generation sequencing was performed for 202 genes in tumor and normal DNA from 257 patients with MBC, including 165 patients with ER/PR+ HER2- (hormone receptor positive, HR+ positive), 32 patients with HER2+ and 60 patients with triple negative (ER/PR/HER2-) cancer. Kaplan Meier survival analysis was performed in our discovery set, in breast cancer patients analyzed in The Cancer Genome Atlas, and in a separate cohort of 98 patients with MBC who underwent clinical genomic testing. Results: Significantly mutated genes (SMGs) varied by histology and tumor subtype, but TP53 was a SMG in all three subtypes. The most SMGs in HR+ patients included PIK3CA (32%), TP53 (29%), GATA3 (15%), CDH1 (8%), MAP3K1 (8%), PTEN (5%), TGFBR2 (4%), AKT1 (4%), and MAP2K4 (4%). TP53 mutations were associated with shorter recurrence-free survival (P=0.004), progression-free survival (P=0.00057) and overall survival (P=0.003). Further, TP53 status was prognostic among HR+ patients with PIK3CA mutations. TP53 mutations were also associated with poorer overall survival in the 442 HR+ breast cancer patients in the TCGA (P=0.042) and in an independent set of 96 HR+ MBC who underwent clinical sequencing (P=0.0004). Conclusions: SMGs differ by tumor subtype but TP53 is significantly mutated in all three breast cancer subtypes. TP53 mutations are associated with poor prognosis in HR+ breast cancer. TP53 mutations should be considered in the design and interpretation of precision oncology trials.

Purpose: Increasing tumor-infiltrating lymphocytes (TIL) is associated with higher rates of pathologic complete response (pCR) to neoadjuvant therapy (NAT) in patients with triple-negative breast cancer (TNBC). However, the presence of TILs does not consistently predict pCR, therefore, the current study was undertaken to more fully characterize the immune cell response and its association with pCR. Experimental Design: We obtained pretreatment core-needle biopsies from 105 patients with stage I–III TNBC enrolled in ARTEMIS (NCT02276443) who received NAT from Oct 22, 2015 through July 24, 2018. The tumor-immune microenvironment was comprehensively profiled by performing T-cell receptor (TCR) sequencing, programmed death-ligand 1 (PD-L1) IHC, multiplex immunofluorescence, and RNA sequencing on pretreatment tumor samples. The primary endpoint was pathologic response to NAT. Results: The pCR rate was 40% (42/105). Higher TCR clonality (median = 0.2 vs. 0.1, P = 0.03), PD-L1 positivity (OR: 2.91, P = 0.020), higher CD3+:CD68+ ratio (median = 14.70 vs. 8.20, P = 0.0128), and closer spatial proximity of T cells to tumor cells (median = 19.26 vs. 21.94 μm, P = 0.0169) were associated with pCR. In a multivariable model, closer spatial proximity of T cells to tumor cells and PD-L1 expression enhanced prediction of pCR when considered in conjunction with clinical stage. Conclusions: In patients receiving NAT for TNBC, deep immune profiling through detailed phenotypic characterization and spatial analysis can improve prediction of pCR in patients receiving NAT for TNBC when considered with traditional clinical parameters.