Page 73 - SRPSKO DRUŠTVO ISTRAŽIVAČA RAKA

SDIRSACR Oncology Insights

L15

Adjuvant therapy options for patients with breast cancer and germline BRCA1/2 mutations

Ivana Božović-Spasojević, MD, PhD

Institute for Oncology and Radiology of Serbia, Belgrade

Keywords: BRCA 1/2 mutations, breast cancer, PARP inhibitors

Backround: Breast cancer is a global health problem and the most common cancer in women in both resource-rich and
resource-limited settings. The lifetime probability of developing invasive breast cancer is approximately one in eight. It
is a heterogeneous, phenotypically diverse disease composed of several biologic subtypes that have distinct behaviors
and responses to therapy.
The use of adjuvant systemic therapy is responsible for much of the reduction in cause-specific mortality from breast
cancer (1).
Pathogenic variants in BRCA1 and BRCA2 are associated with significantly elevated lifetime risks of breast, ovarian,
pancreatic, and prostate cancer (2,3). These genes are critical in double-strand break repair through homologous
recombination. An understanding of the biology of BRCA1 and BRCA2 led to the development of targeted therapeutics,
specifically poly(ADP-ribose) polymerase (PARP) inhibitors, which have been approved by the US Food and Drug
Administration for multiple BRCA1/2-associated cancers.

Main findings
The development of poly(ADP-ribose) polymerase inhibitors (PARPi) for BRCA1/2 mutation carriers has been a major
advance in targeted therapeutics for tumor suppressor genes by deploying the concept of synthetic lethality. Synthetic
lethality refers to cell death with inhibition or gene alteration of two DNA damage response pathways, but not with
alteration in either pathway alone. Synthetic lethality allows for the targeting of tumor suppressor genes with the
potential for limited toxicity in heterozygous cells. In 2005, two seminal studies were published demonstrating that
synthetic lethality could be leveraged in BRCA1/2-deficient tumors: cells deficient in homologous recombination (HR)
were killed when PARP was inhibited (4,5). Clinical efforts followed, and the phase I trial of the PARPi olaparib was
published in 2009, which demonstrated objective responses in advanced breast, ovarian, and prostate cancer patients
with gBRCA1/2 (6). Subsequent studies led to the regulatory approval of multiple PARPi (i.e., olaparib, niraparib,
rucaparib, and talazoparib) for the treatment of gBRCA1/2-associated breast, pancreatic, prostate, and ovarian cancer.

Early HER2 negative breast cancer, adjuvant therapy
A randomized, double-blind trial, OlympiA, was conducted in 1836 patients with high-risk, HER2-negative early breast
cancer with BRCA1 or BRCA2 pathogenic variants and high-risk clinicopathologic factors who had received local
treatment and neoadjuvant or adjuvant chemotherapy (7).
High risk features, according to the OlympiA eligibility criteria, are the following:
a. for the triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy patient must have residual
disease to be eligbe for adjuvant olaparib, while for patients treated with adjuvant chemotherapy, to have higher-
risk features patient must to have either node-positive disease or a primary tumor ≥2 cm on the surgical specimen;
b. for the hormone receptor-positive disease treated with neoadjuvant chemotherapy patients with residual disease
and a CPS+EG≥3 (the pretreatment clinical stage and post-treatment pathologic stage, as well as estrogen receptor
status and tumor grade, CPS+EG score) were considered as eligable, while for patients treated with adjuvant
chemotherapy high risk was considered as of N2 disease.
Olaparib treatament was given for one year at the dose of 300 mg twice daily, orally.
In this trial, patients assigned to the olaparib group had an improvement in three-year DFS relative to the placebo
group (86 vs 77%; difference, 8.8%; 95% CI 4.5-13.0); distant DFS at three years was 88% in the olaparib group and
80% in the placebo group (difference, 7.1%; 95% CI 3.0-11.1); four-year overall survival was 90 vs 86% (HR 0.68, 98.5%
CI 0.47-0.97) (8). The benefit of adjuvant olaparib relative to placebo was observed for invasive DFS irrespective of
the germline BRCA mutation (BRCA1 vs BRCA2), hormone receptor status, carboplatin administration, or whether
chemotherapy was administered in the neoadjuvant versus adjuvant setting.
These data justify genetic testing for all patients meeting the OlympiA eligibility criteria. Olaparib has regulatory
approval by the US Food and Drug Administration for the adjuvant treatment of adult patients with deleterious
germline BRCA-mutated, HER2-negative, high-risk early breast cancer who have been treated with neoadjuvant or
adjuvant chemotherapy.

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