Toxicity of (neo)adjuvant chemotherapy for BRCA1- and BRCA2-associated breast cancer

Abstract

Treatment with (neo)adjuvant chemotherapy for breast cancer, as currently given, causes cell damage by induction of double-strand DNA breaks. Because BRCA1 and BRCA2 proteins play a role in the repair of DNA damage, the efficacy of (neo)adjuvant chemotherapy may be increased in BRCA1/2-associated breast cancer patients. As a downside, acute chemotherapy-related toxicity may also be increased. We selected all female patients who were treated at the Erasmus MC Cancer Institute, with (neo)adjuvant chemotherapy for primary or locoregional recurrence of breast cancer (PBC/LR) between January 1, 2004 and December 31, 2014. The primary outcome was the relative total dose intensity (RTDI), calculated for anthracyclines and taxanes separately. Secondary outcomes were the occurrence of febrile neutropenia, delay in chemotherapy administration, and switch to another chemotherapy regimen due to toxicity. In total, 701 patients treated for PBC/LR were eligible for data analyses, among which 85 BRCA1/2 mutation carriers (n = 67 BRCA1 and n = 18 BRCA2). The mean RTDI for anthracyclines was not significantly different between both groups (98.7 % in the BRCA1/2, 96.6 % in the sporadic group, p = 0.27). Also the mean RTDI for taxanes was not significantly different between the groups (93.6 % in the BRCA1/2-associated, 90.0 % in the sporadic group, p = 0.12). Linear regression analysis revealed no significant effect of BRCA1/2 mutation carriership on the RTDIs. No significant differences were found in the percentages of patients presenting with febrile neutropenia, having a delay in chemotherapy administration or switching to an altered chemotherapy regimen. Additionally, the odds ratios showed no significant effect of BRCA1/2 mutation carriership on the secondary outcome variables. (Neo)adjuvant chemotherapy-related toxicity was not different between BRCA1/2-associated and sporadic breast cancer patients suggesting that the DNA damage repair mechanism of non-cancer cells with only one normal copy of either the BRCA1 or BRCA2 gene is sufficiently functional to handle acute chemotherapy-associated toxicity.

Hematologic toxicity in BRCA1 and BRCA2 mutation carriers during chemotherapy: A retrospective matched cohort study

“…Small studies have reported conflicting data as to whether women with a single inherited mutation in BRCA1 or BRCA2 experience excess hematologic toxicity during cytotoxic chemotherapy . Reported toxicities included more frequent dose‐limiting neutropenia and neutropenic fever, cases of therapy‐related leukemia, and lower baseline blood counts.…”

“…Reported toxicities included more frequent dose‐limiting neutropenia and neutropenic fever, cases of therapy‐related leukemia, and lower baseline blood counts. However, conclusions were limited by small sample size, lack of a comparable control population, and/or inability to evaluate those with BRCA1 vs BRCA2 mutations separately . Thus, we performed a multicenter, retrospective, matched cohort study to compare the frequency, severity, and timing of hematologic toxicities occurring throughout the multicycle curative intent chemotherapeutic regimens for breast cancer in women with and without an inherited BRCA1 or BRCA2 mutation.…”

“…Small studies have reported conflicting data as to whether women with a single inherited mutation in BRCA1 or BRCA2 experience excess hematologic toxicity during cytotoxic chemotherapy. [10][11][12] Reported toxicities included more frequent dose-limiting neutropenia and neutropenic fever, cases of therapy-related leukemia, and lower baseline blood counts. However, conclusions were limited by small sample size, lack of a comparable control population, and/or inability to evaluate those with BRCA1 vs BRCA2 mutations separately.…”

Total choline quantification measured by 1H MR spectroscopy as early predictor of response after neoadjuvant treatment for locally advanced breast cancer: The impact of immunohistochemical status

“…The usual neoadjuvant schema for locally advanced breast cancer consists of anthracycline followed by taxane‐based treatment, even if this sequence has been questioned recently . However, considerable toxicity is related with NAC, particularly with respect to anthracyclines due to induction of double‐strand DNA breaks and DNA damage in cancer, but also in normal cells . Therefore, detecting nonresponse early is important for clinicians to make therapeutic decisions and to avoid prescribing toxic treatments to patients who will not benefit from them.…”

“…15 However, considerable toxicity is related with NAC, particularly with respect to anthracyclines due to induction of double-strand DNA breaks and DNA damage in cancer, but also in normal cells. 16 Therefore, detecting nonresponse early is important for clinicians to make therapeutic decisions and to avoid prescribing toxic treatments to patients who will not benefit from them. Additionally, predicting the size of the residual tumor after NAC is important for planning the type of surgery: lumpectomy versus mastectomy.…”