Thus the preclinical and clinical data are consistent with the emerging understanding of BRCA1 function in DNA-damage response and cell cycle regulation. While these findings raise the possibility that germline status may influence treatment choices, there is insufficient evidence at this time to support treating mutation carriers with different regimens.
Another specific process to exploit in BRCA1/BRCA2-deficient tumors is the poly (ADP-ribose) polymerase (PARP) pathway. Whereas BRCA1 and BRCA2 are active in the repair of double-stranded DNA breaks by homologous recombination, PARP is involved in the repair of single-stranded breaks by base excision repair. It was hypothesized that inhibiting base excision repair in BRCA1 or BRCA2 deficient cells would lead to enhanced cell death as two separate repair mechanisms would be compromised-the concept of synthetic lethality. In vitro studies have shown that PARP inhibition kills BRCA mutant cells with high specificity.[249,250]
PARP inhibitors quickly entered clinical trials. A phase I study of an oral PARP inhibitor called olaparib has demonstrated tolerability (with minimal side effects) and activity in BRCA1 and BRCA2 mutation carriers with breast, ovarian, and prostate cancer. Phase II trials in breast cancer have confirmed tolerability and efficacy of olaparib in mutation carriers.[252,253] Two sequential cohorts of 27 patients, each receiving 400 mg twice daily of olaparib and 100 mg twice daily of olaparib, respectively, were examined. The women had received a median of three prior chemotherapeutic regimens. Responses were seen in both groups. In the 400 mg twice daily group, 41% (11/27) of patients had a RECIST-defined response, and another 44% (12/27) had stable disease. In the 100 mg twice daily group, 22% (6/27) had responses, and 44% (12/27) had stable disease. Although the two doses levels cannot be directly compared as they were not randomized, more responses were seen in the higher dose cohort. Several other PARP inhibitors are in development.
Preclinical models suggest that the combination of PARP inhibitors and chemotherapy may be synergistic;[254,255] however, such synergy may come at the expense of toxicity. The results of ongoing and recently completed clinical trials are awaited with interest.
Breast conservation therapy for BRCA1/BRCA2 mutation carriers
While lumpectomy plus radiation therapy has become standard local-regional therapy for women with early stage breast cancer, its use in women with a hereditary predisposition for breast cancer who do not choose immediate bilateral mastectomy is less clear. Concern about its use, particularly in women with deleterious BRCA1 or BRCA2 mutations, centers around two issues. The first is the potential for an increased rate of ipsilateral cancers in the treated breast. The second is the potential for therapeutic radiation to induce tumors in BRCA1/BRCA2 defective cells. Most of the early studies that used family history of breast/ovarian cancer as a surrogate for hereditary risk failed to find an increase in ipsilateral cancers in women treated with breast conservation therapy.[256,257,258,259,260] However, with the availability of clinical genetic testing for BRCA1/BRCA2 mutations, treatment outcomes for carriers of deleterious mutations in BRCA1/BRCA2 can now be compared with those of noncarriers.