Therapy Related Myeloid and Lymphoid Neoplasms in BRCA Mutated Breast and Ovarian Cancer Patients

Background

The treatment of breast and ovarian cancer is associated with a small risk of therapy related myeloid/lymphoid neoplasms (t-MLN).The outcomes of t-MLN are dismal. It is unknown whether germline mutations in DNA damage repair mechanisms increase the risk of t-MLN when patients are exposed to chemotherapy and/or radiation therapy. Germline mutations in BRCA1 and BRCA2 reduce the ability of both neoplastic and normal cells to repair of DNA damage from environmental stressors or chemotherapy. Mutations in TP53, another DNA damage repair gene, have been demonstrated to be selected for by chemotherapy and be associated with t-MLN. Therefore, we hypothesize that breast and ovarian cancer patients with germline mutations in BRCA1 and BRCA2 are at higher risk for developing t-MLN when compared to the patients receiving chemotherapy and/or radiation therapy for breast or ovarian cancer without BRCA 1 and BRCA 2 germline mutations.

Methods

Under an IRB approved protocol patients with BRCA1/2 mutated breast or ovarian cancer treated at West Cancer Center (WCC) between January 2006 to December 2015 were identified using a genetic database search. Demographics were obtained including age of diagnosis, specific BRCA germline mutation, chemotherapy or targeted therapy used, receipt of radiation therapy, and stage of disease. t-MLN was defined as any myeloid malignancy or acute lymphoblastic leukemia (MDS, AML or ALL) diagnosed with a latency of at least 12 months after receipt of the first dose of chemotherapy or radiation therapy. Patients that were identified that did not receive therapy were also evaluated and followed for incidence of second primary malignancy. The incidence of t-MLN for patients diagnosed with BRCA mutated breast or ovarian cancer was compared to the reported expected incidence of t-MLN from the SEER database (MP-SIR session, SEER 9 Nov 2015, 1973-2013) for the corresponding time period. Patients will continue to be followed through the electronic medical record (EMR) for up to 10 years from the receipt of therapy. Analyses were conducted used Microsoft Excel 14.5.7, Seer*STAT and GraphPad prism version 6. The dataset will be updated annually for t-MLN incidence.

Results

Seventy-Eight patients with BRCA mutated breast or ovarian cancers were identified with median follow up of 3.3 (range 0.6 - 13.9) years from date of diagnosis. Seventy-seven patients were female and one was male. Median age was 47 (25-74). 70% (n = 55) patients were Caucasians, 26% (n = 20) were African-Americans and 4% were others (n = 3). 72% (n = 56) patients had breast cancer, 22% (n = 17) had ovarian cancer and 6% (n = 5) had both. BRCA mutations were distributed with 49% (n = 38) BRCA1 and 51% (n = 40) BRCA2. 46% (n = 28) of breast cancer had BRCA1 mutations and 54% (n = 33) had BRCA2 mutations. 55% (n = 12) of ovarian cancer had BRCA1 mutations and 45% (n = 10) had BRCA2 mutations. Stage distribution of breast cancer patients was, stage I 30% (n = 18), stage II 38% (n = 23), stage III 19% (n = 11), stage IV 5% (n = 3) and stage was unknown in 8% (n = 5). Stage distribution of ovarian cancer patients was, stage I 5% (n = 1), stage II 10% (n = 2), stage III 50% (n = 11), stage IV 35% (n = 8). 93% (n = 57) of breast cancer patients received chemotherapy including 66% (n = 40) that received anthracycline-containing regimens. 7% (n = 4) of breast cancer patients received no chemotherapy. 100% (n = 22) of ovarian cancer patients received chemotherapy and 100% of them received platinum containing regimens. 44% (n = 27) of patients received radiation therapy (all breast cancer). One patient (1.3%) with a BRCA1 mutation 1996ins4 and stage IV ovarian cancer developed t-AML after receiving five lines of therapy including olaparib 66 months after receipt of first chemotherapy and succumbed to her disease one month later. During the same time period (2006+) 14 women (0.6%) in the SEER database developed t-MLN (13 AML and 1 ALL) out of 2,533 women with a diagnosis of breast cancer. There is no observed difference in the incidence of t-MLN in our BRCA1/2 germline mutated patients and the SEER population (Fisher's exact 0.366, Odds ration 2.34 [0.30-18]).

Conclusion:

With 3.3 years of median follow-up our dataset is still immature but to date there is no observed increased risk of t-MLN in patients with BRCA1/2 germline mutations. We will continue to follow these women prospectively for further events and update the dataset annually.