Rapid selection of BRCA1-proficient tumor cells during neoadjuvant therapy for ovarian cancer in BRCA1 mutation carriers

Abstract

Ovarian carcinomas (OC) often demonstrate rapid tumor shrinkage upon neoadjuvant chemotherapy (NACT). However, complete pathologic responses are very rare and the mechanisms underlying the emergence of residual tumor disease remain elusive. We hypothesized that the change of somatic BRCA1 status may contribute to this process. The loss-of-heterozygosity (LOH) at the BRCA1 locus was determined for 23 paired tumor samples obtained from BRCA1 germ-line mutation carriers before and after NACT. We observed a somatic loss of the wild-type BRCA1 allele in 74% (17/23) of OCs before NACT. However, a retention of the wild-type BRCA1 copy resulting in a reversion of LOH status was detected in 65% (11/17) of those patients after NACT. Furthermore, we tested 3 of these reversion samples for LOH at intragenic BRCA1 single nucleotide polymorphisms (SNPs) and confirmed a complete restoration of the SNP heterozygosity in all instances. The neoadjuvant chemotherapy for BRCA1-associated OC is accompanied by a rapid expansion of pre-existing BRCA1-proficient tumor clones suggesting that continuation of the same therapy after NACT and surgery may not be justified even in patients initially experiencing a rapid tumor regression.

Atl

“…6 In addition, there are some other well-established mechanisms of acquired chemotherapy resistance in cancers arising in BRCA1 mutation carriers. 5 The most known root for tumor escape from platinum therapy involves the emergence of secondary mutation, which affects the inherited pathogenic allele and is located in the vicinity to the first mutation.…”

“…6,27 The conventional NACT regimens have high activity towards BRCA1-deficient cells but cannot effectively eradicate the residual cells with intact BRCA1 function. 6 Combination of platinum therapy with other drugs, whose activity is not limited to BRCA1-deficient cells, may be a viable approach, both for dealing with the issue of intratumoural heterogeneity 6,27 and for prevention of tumor evolution under systemic therapy. 5,20Y22 Use of platinum-taxane doublets, which is a current standard for the treatment of nonselected OC patients, does not seem to be superior to other regimens in BRCA1 mutation carriers (Table 4).…”

“…However, this approach may not be suitable for BRCA1-related OCs, assuming that post-NACT residual tumor masses are no longer BRCA1-deficient and therefore are unlikely to respond to platinum agents. 6,20 Given that presence of BRCA1 LOH in the tumor tissue is predictive for chemotherapy response, 15 the determination of LOH status in the surgically removed cancer masses may help to guide adjuvant treatment regimens. If BRCA1 LOH is retained even after surgery, the residual cells are likely to remain BRCA1deficient, and therefore, the continuation of the platinumbased therapy appears to be justified.…”

“…4 For example, BRCA1associated OCs contain a fraction of BRCA1-proficient cells even in chemotherapy-naive tumors, and these clones rapidly repopulate tumor masses during NACT. 6 Not surprisingly, the majority of OC treated by NACT, surgery, and adjuvant therapy inevitably relapse, unless the NACT results in complete pathologic response. 4 In addition to pCR, it has been acknowledged that complete cytoreduction during interval debulking surgery is a significant predictor of prolonged relapse-free survival.…”

Molecular Diagnostics in Clinical Oncology

“…In accordance with this mechanism, somatic loss of the normal BRCA1/2 allele correlates with drug sensitivity of tumors arising in BRCA1/2 mutation carriers (Maxwell et al, 2017). Furthermore, the development of resistance to cisplatin or PARPi involves restoration of BRCA1/2 function, achieved either by the second mutation in the affected copy of the gene or selection of pre-existing BRCA1-proficient tumor cells (Lord and Ashworth, 2013; Sokolenko et al, 2017). …”