Carboplatin Hypersensitivity Linked to BRCA Deficiency in Ovarian Cancer

Gary H. Altwerger, MD

Treatment with a carboplatin desensitization regimen led to improved overall survival (OS) in patients with BRCA-proficient ovarian cancer, according to a retrospective analysis reported at the 2017 Society of Gynecologic Oncology Annual Meeting.

Patients with BRCA-proficient cancers and treated hypersensitivity had a median OS of 114 months compared with 71 months for patients with BRCA-proficient cancers and no carboplatin hypersensitivity. Carboplatin hypersensitivity had a strong association with BRCA deficiency, but desensitization did not improve survival as compared with patients who did not have carboplatin hypersensitivity, Gary H. Altwerger, MD, a gynecologic oncology fellow at Yale University School of Medicine, and colleagues reported in a poster presentation.

“Patients who undergo carboplatin desensitization have better overall survival than patients who did not undergo the glucocorticoid and antihistamine regimen,” the investigators concluded. “Patients with germline BRCA1/2 proficiency and hypersensitivity who received carboplatin desensitization have better median overall survival compared with the same patients who do not have hypersensitivity. Importantly, there is no difference in median overall survival in patients with germline BRCA1/2 deficiencies when comparing patients with or without hypersensitivity.

“This study supports the use of a carboplatin desensitization protocol, as it is effective and safe at preventing hypersensitivity reactions and also improves overall survival in patients with advanced-stage ovarian cancer.”

A mainstay of treatment for ovarian cancer, carboplatin induces tumor cell death by means of DNA double-strand breaks. Double-strand breaks activate DNA repair mechanisms, including the BRCA homologous recombination (HR) repair enzymes. Patients with BRCA mutations have better clinical outcomes when treated with carboplatin-containing chemotherapy, in part, because of the accumulation of DNA damage in HR-deficient patients, Altwerger and colleagues noted.

A potential downside to carboplatin therapy is hypersensitivity reactions after exposure to multiple cycles of therapy. Carboplatin desensitization protocols can quickly and efficiently prevent hypersensitivity reactions.

Previous research suggested an association between carboplatin, PARP inhibition, BRCA deficiency, and hypersensitivity (Br J Cancer. 2013;109:1072-1078). Dr. Altwerger and colleagues investigated overall survival in patients with BRCA-deficient and proficient ovarian cancer and carboplatin hypersensitivity treated with a desensitization protocol.

The retrospective study included patients treated from August 2012 to January 2016. All patients underwent testing for germline BRCA mutations. Treatment in all cases included carboplatin, and all patients were evaluated for carboplatin hypersensitivity during the seventh cycle of therapy and beyond.

The analysis included 40 patients with BRCA-deficient tumors and 51 with BRCA-proficient tumors. The BRCA-deficient group included 8 patients with breast cancer.

Significantly more patients in the BRCA-deficient group had carboplatin hypersensitivity (31 versus 20 in the BRCA-proficient group, P =.0003).

The entire study population had a median OS of 127 months, 5-year OS of 72%, and 10-year OS of 51%. Patients with BRCA deficiency had a significantly better median OS compared with the BRCA-proficient group (176 vs 83 months; P = .0249). Patients with treated carboplatin hypersensitivity had a median OS of 131 months compared with 83 months for patients without sensitivity to carboplatin (P = .0094).

Evaluating BRCA status and hypersensitivity, investigators found that the BRCA-deficient group had a median OS of 176 months with treated carboplatin hypersensitivity versus 163 months without hypersensitivity, a nonsignificant difference. In contrast, patients with BRCA proficiency and treated carboplatin hypersensitivity had a median OS of 114 months compared with 71 months for patients without carboplatin hypersensitivity (P = .04943).

Comparison of clinical and demographic characteristics between carboplatin-hypersensitive and nonhypersensitive patients showed no significant differences in either the BRCA-deficient or BRCA-proficient group.

“We have shown that germline BRCA1/2 deficiencies are indeed a risk factor, independent of PARP inhibitors, for the development of carboplatin hypersensitivity,” the investigators concluded. “These findings suggest, overall, a link between carboplatin-induced DNA damage, the immune system, and hypersensitivity reactions. Future studies are necessary to determine the role of DNA damage in the development of hypersensitivity reactions to chemotherapy.”