Clinicopathological characteristics and eligibility for adjuvant olaparib of germline BRCA1/2 mutation carriers with HER2-negative early breast cancer

Following the survival benefit demonstrated in the OlympiA trial, one year of adjuvant olaparib is now recommended for all patients with germline BRCA1/2 pathogenic/likely pathogenic

variants (PV) and high-risk, HER2-negative early breast cancer after chemotherapy. However, optimal identification of high-risk patients who may derive benefit from this genomically-directed

therapy is debated. In this study, we sought to characterize the real-world proportion of gBRCA1/2 PV carriers eligible for adjuvant olaparib according to the OlympiA criteria, and to

compare clinicopathologic characteristics and outcomes between eligible and ineligible patients.

Approximately 5% of breast cancers occur in patients who carry a germline BRCA1/2 (gBRCA1/2) pathogenic or likely pathogenic variant (PV)1,2. In the OlympiA trial one year of adjuvant

olaparib improved invasive disease-free survival (iDFS) and overall survival (OS) in gBRCA1/2 PV carriers with high-risk, HER2-negative early breast cancer3,4, and olaparib became the first

systemic adjuvant therapy specifically approved for these patients. Eligibility criteria of OlympiA differed for triple-negative breast cancer (TNBC) and hormone receptor-positive (HR+)

tumors. Patients with TNBC were eligible either when residual disease was present after neoadjuvant chemotherapy, or after upfront surgery and adjuvant chemotherapy for tumors ≥2 cm or with

nodal involvement. Patients with HR+ tumors were eligible either if there was residual disease and a clinical and pathologic stage (CPS) and estrogen receptor status and histologic grade

(EG) (CPS + EG) score ≥3 after neoadjuvant chemotherapy, or if ≥4 nodes were involved at surgery prior to adjuvant chemotherapy.

Whether these criteria identify all gBRCA PV carriers with high-risk breast tumors who may benefit from olaparib is debated. This is particularly relevant for HR+ breast cancers, as

alternative trials used different criteria to select high-risk patients. In monarchE, for instance, patients were eligible either if they had ≥4 positive nodes at surgery, or 1-3 positive

nodes and at least one additional high-risk criterion among grade 3 disease, tumor size > 5 cm, or Ki67 ≥ 20%. In this study, we used a prospectively maintained single institution database

to characterize the real-world proportion of gBRCA1/2 PV carriers with early breast cancer who meet OlympiA inclusion criteria, and compared clinicopathologic characteristics and outcomes

between eligible and ineligible patients. Additionally, we investigated the overlap between criteria in OlympiA and monarchE in an effort to identify additional high-risk patients who might

benefit from novel targeted therapies in the adjuvant setting.

We identified 205 gBRCA1/2 PV carriers with newly diagnosed, HER2-negative early breast cancer, including 113 with HR+ and 92 with TNBC (Fig. 1, Supplementary Table 1). Of them, 15 had

synchronous primaries for which only the highest risk tumor was considered in the analysis. Median age at diagnosis was 43 years and most patients (n = 129, 62.9%) were premenopausal. A

gBRCA1 PV was identified in 115 (56.1%) patients and a gBRCA2 PV in 90 (43.9%). Overall, 73 (35.6%) patients underwent genetic testing before the diagnosis of breast cancer. A total of 166

(81.0%) patients received chemotherapy; of them, 130 (78.3%) received an anthracycline-containing regimen and 32 (19.3%) received platinum. Neoadjuvant chemotherapy was administered to 107

patients (77 gBRCA1, 30 gBRCA2), of whom 47 (40 gBRCA1, 7 gBRCA2) achieved a pCR (43.9%). Only 8 (3.9%) patients received immunotherapy. Eleven patients received (neo)adjuvant PARP

inhibitors, and 4 participated in the OlympiA trial.

BC breast cancer, DCIS ductal carcinoma in situ, gBRCA PV germline BRCA pathogenic or likely pathogenic variant, HER2 human epidermal growth factor receptor 2, HR+ hormone receptor positive,

pCR pathologic complete response, TNBC triple-negative breast cancer.

Overall, 60 (29.3%) patients were eligible for adjuvant olaparib according to OlympiA criteria (39 gBRCA1 and 21 gBRCA2 PV carriers), including 40 (66.7%) with TNBC and 20 (33.3%) with HR+

breast cancer (Table 1; Fig. 2).

a iDFS for patients eligible and ineligible for adjuvant olaparib; b RFS for patients eligible and ineligible for adjuvant olaparib; c Proportion of eligible and ineligible patients among

gBRCA PV carriers with TNBC; d Proportion of eligible and ineligible patients among gBRCA PV carriers with HR+/HER2− breast cancer. iDFS invasive disease-free survival, RFS recurrence-free

survival, HER2− human epidermal growth factor receptor 2 negative, HR+ hormone receptor positive, PV pathogenic/likely pathogenic, TNBC triple-negative breast cancer.

Major reasons why most patients identified with gBRCA1/2 PV and breast cancer were deemed ineligible for adjuvant olaparib were lack of prior chemotherapy (n = 9), low anatomic stage at

upfront surgery (n = 16 with stage I TNBC; n = 63 with HR+ tumors and