The Efficacy of Taxane Chemotherapy for Metastatic Breast Cancer in BRCA1 and BRCA2 Mutation Carriers

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1 The Efficacy of Taxane Chemotherapy for Metastatic Breast Cancer in BRCA1 and BRCA2 Mutation Carriers Mieke Kriege, PhD 1 ; Agnes Jager, MD, PhD 1 ; Maartje J. Hooning, MD, PhD 1 ; Elisabeth Huijskens 1 ; Jannet Blom 1 ; Carolien H. M. van Deurzen, MD, PhD 2 ; Marijke Bontenbal, MD, PhD 1 ; J. Margriet Collee, MD 3 ; Marian B. E. Menke-Pluijmers, MD, PhD 4 ; John W. M. Martens, PhD 1 ; and Caroline Seynaeve, MD, PhD 1 BACKGROUND: We assessed the efficacy of taxane chemotherapy in BRCA1- and BRCA2-associated patients compared with sporadic metastatic breast cancer patients. METHODS: Response rates (RRs) to and progression-free survival (PFS) after taxane chemotherapy of 35 BRCA1-associated and 13 BRCA2-associated metastatic breast cancer patients were compared with those outcomes in 95 matched (1:2) sporadic patients. Matching was performed for age at and year of diagnosis of primary breast cancer, year of metastatic disease, and line of therapy (first vs second or third). RESULTS: Among BRCA1-associated patients, the RR was worse (objective response [OR], 23% vs 38%; progressive disease [PD], 60% vs 19%; P < 0.001); and the median PFS shorter (2.2 vs 4.9 months; P ¼ 0.04) compared with sporadic patients. In the subgroup of hormone receptor (HRec)-negative patients, BRCA1-associated patients (n ¼ 20) had a worse RR (OR, 20% vs 42%, respectively; PD, 70% vs 26%, respectively; P ¼ 0.03) and a shorter PFS (1.8 vs 3.8 months; P ¼ 0.004) compared with sporadic patients (n ¼ 19). These outcomes in HRec-positive patients were similar in BRCA1-associated (n ¼ 11) and sporadic (n ¼ 61) patients (OR, 36% vs 38%; PD, 28% vs 20%; median PFS, both 5.7 months). In BRCA2-associated patients, who were mainly HRec-positive, the OR was higher than in sporadic patients (89% vs 38%, respectively; P ¼ 0.02), whereas the median PFS was not significantly different (7.1 vs 5.7 months, respectively). CONCLUSIONS: BRCA1-associated, HRec-negative metastatic breast cancer patients were less sensitive to taxane chemotherapy than sporadic HRec-negative patients. HRec-positive BRCA1- and BRCA2- associated patients had a sensitivity to taxane chemotherapy similar to that of sporadic patients. Cancer 2012;118: VC 2011 American Cancer Society. KEYWORDS: BRCA1, BRCA2, breast cancer, metastatic disease, docetaxel, paclitaxel. The taxanes paclitaxel and docetaxel are microtubule-stabilizing agents that have become widely recognized as active cytotoxic agents for the treatment of early and advanced breast cancer. 1-3 A recent meta-analysis has shown that the addition of a taxane to an anthracycline-based regimen improves disease-free and overall survival of high-risk early breast cancer patients. 2 In advanced disease, treatment with taxane chemotherapy has shown response rates (RRs) between 35% and 60% and a time to progression of 5-9 months, depending on pretreatment with anthracyclines and line of therapy given. 3 However, the downsides of taxane chemotherapy are the possibly serious side effects such as neutropenic fever, muscle cramps, peripheral neuropathy, and relevant fatigue. 3 Growing evidence from preclinical studies suggests that sensitivity to taxanes requires a functional BRCA1 protein. 4-7 In response to the abnormal mitosis induced by taxanes, BRCA1 protein activates the mitotic spindle checkpoint and promotes apoptosis mediated by the c-jun N-terminal kinase/stress-activated protein kinase pathway, leading to cell death. 8,9 Until now, for the BRCA2 protein there is no evidence for a pathophysiological link with the efficacy of taxanes. Clinical data confirming these preclinical findings are very scarce. In a neo-adjuvant study, the percentage of patients achieving a partial or complete response after treatment with docetaxel in combination with doxorubicin was lower in Corresponding author: Mieke Kriege, PhD, Department of Medical Oncology, Rotterdam Family Cancer Clinic, Erasmus MC-Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, Netherlands; Fax: (011) ; a.kriege@erasmusmc.nl 1 Family Cancer Clinic, Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Centre, Rotterdam, Netherlands; 2 Family Cancer Clinic, Department of Pathology, Erasmus MC, Rotterdam, Netherlands; 3 Family Cancer Clinic, Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands; 4 Family Cancer Clinic, Department of Oncological Surgery, Erasmus MC-Daniel den Hoed Cancer Centre, Rotterdam, Netherlands DOI: /cncr.26351, Received: March 16, 2011; Accepted: May 9, 2011, Published online July 14, 2011 in Wiley Online Library (wileyonlinelibrary.com) Cancer February 15,

2 BRCA1-associated compared with sporadic breast cancer patients (in 6/15 vs 12/12 patients, respectively; P ¼ 0.001). 10 In another retrospective, neo-adjuvant study among BRCA1 mutation carriers, treatment with taxanebased therapy resulted in a low percentage of pathologic complete responses (2/25 [8%] patients), whereas this percentage was 22% for antracycline-based therapy (11/ 51 patients) and 83% after cisplatin monotherapy (10/12 patients), suggesting inferior chemosensitivity to taxane chemotherapy for BRCA1 mutation carriers. 11 Regarding metastatic breast cancer, it has been reported that patients with loss of BRCA1 protein expression (n ¼ 13) determined via immunohistochemistry have a shorter progression-free survival (PFS) after taxane chemotherapy compared with patients with BRCA1 protein expression (n ¼ 6) (6.5 vs 14.7 months, respectively). 12 However, the relevance of this finding is unclear, because measuring BRCA1 protein expression by immunohistochemistry is inaccurate and can lead to an overestimation of patients with loss of BRCA1 protein expression, and loss of BRCA1 protein expression does not necessarily imply dysfunctional BRCA1 protein. Regarding BRCA2, it has been reported in a small study (n ¼ 25) that a low as opposed to a high BRCA2 messenger RNA (mrna) level was correlated with a higher RR to taxane chemotherapy. 13 Aiming at improved treatment for BRCA mutation carriers, it is crucial to obtain more clinical data on the efficacy of taxane chemotherapy in BRCA mutation carriers. Therefore, we investigated the RR and PFS in BRCA1- and BRCA2-associated compared with sporadic metastatic breast cancer patients. MATERIALS AND METHODS Using the database of the Family Cancer Clinic of the Erasmus MC-Daniel den Hoed Cancer Center, we identified all female patients with invasive breast cancer belonging to a BRCA1 or BRCA2 mutation family and having been treated with docetaxel or paclitaxel for metastatic disease, irrespective of treatment line (n ¼ 48). Selected patients included proven BRCA1 or BRCA2 mutation carriers (n ¼ 41), as well as obligate mutation carriers (n ¼ 1) and first-degree family members of mutation carriers diagnosed with breast cancer 55 years of age who had not been tested themselves (n ¼ 6). Each BRCA-associated patient was matched with 2 sporadic breast cancer patients derived from the institutional registry. Patients were matched for age at and year of primary breast cancer diagnosis (within 5 years), year of diagnosis of metastatic disease (within 5 years), line of administration of taxane chemotherapy (first line vs second or third line), and concomitant trastuzumab treatment (yes/no). Patients diagnosed with a second primary breast cancer within 10 years after the first primary cancer (n ¼ 10) were matched for age at and year of diagnosis of the first breast cancer, whereas patients diagnosed with a second primary breast cancer 10 years or more after the first primary cancer (n ¼ 4) were matched for age at and year of diagnosis of the second primary breast cancer. Medical records from the potentially eligible sporadic breast cancer patients were evaluated for family cancer history. Patients with sporadic breast cancer were excluded if they had 2 additional family members with breast cancer (irrespective of age), or 1 additional family member diagnosed with breast cancer under the age of 50 years or with ovarian cancer (any age). The study was approved by the Medical Ethical Committee of the Erasmus University Medical Center, Rotterdam, and the Netherlands (MEC ). For each patient, data on patient and tumor characteristics, adjuvant systemic treatment, disease recurrence, type of and response to treatment for metastatic disease, and death were extracted from the medical records. For patients diagnosed with a second primary breast cancer within 10 years after the first breast cancer, tumor characteristics of the first breast cancer were considered. In the other 4 cases, the characteristics of the second primary breast cancer were considered. Taxane chemotherapy for metastatic disease could have been given as first-, second-, or third-line chemotherapy. Docetaxel was given every 3 weeks (100 mg/ m 2 ) or weekly (30-36 mg/m 2 ), while paclitaxel was administered either every 3 weeks (175 mg/m 2 )orina weekly regimen (90 mg/m 2 on days 1, 8, and 15, repeated every 4 weeks). Response evaluation was performed after every 2 or 3 cycles of chemotherapy, or earlier in case of symptoms suggestive of progressive disease. Response was assessed by means of International Union Against Cancer criteria, 14 because a large portion of the patients were treated before the introduction of the RECIST criteria in Objective response (OR) was defined as complete response (CR) (disappearance of all known disease) or partial response (PR) (50% decrease in measurable lesions and objective improvement in evaluable lesions). Stable disease was defined as lesions unchanged (ie, <50% decrease and <25% increase in the size of measurable lesions). 900 Cancer February 15, 2012

3 Taxanes for BRCA1/2 Breast Cancer/Kriege et al Progressive disease (PD) was defined as progression of some or all lesions (25% increase) and/or appearance of new lesions. In case of response or the absence of PD, chemotherapy was given for 6 cycles in total. Continuation of chemotherapy was dependent on toxic adverse effects and the discretion of the treating physician. After the introduction of trastuzumab as evidence-based therapy, taxane chemotherapy was administered in combination with trastuzumab for patients with Her-2/neu positive breast cancer (2 BRCA1, 4 sporadic). Patients with estrogen-positive breast cancer who stopped taxane chemotherapy and who were still responding received endocrine therapy as consolidation therapy. Differences in patient and tumor characteristics were analyzed using the Student t test (continuous variables) or Pearson s chi-square test (categorical variables). Differences in RR between BRCA1-associated and sporadic tumors were tested using a chi-square test for trend (linear-by-linear association). PFS after taxane chemotherapy was defined as the period between the start of chemotherapy and date of PD, and was assessed by the Kaplan-Meier survival method. Using the Cox proportional hazard regression model, PFS was multivariately assessed, adjusting for possible confounding factors, including hormone receptor (HRec) status (negative/positive), adjuvant chemotherapy (yes/no), and site of first relapse (visceral/bone/soft tissue). A negative HRec status was defined as negativity of both estrogen receptor (ER) and progesterone receptor (PR), and a positive HRec status was defined as ER and/or PR being positive. HRec status was considered as unknown if information on both ER and PR status was lacking, or in case of negative ER and unknown PR status. A cut-off level of 10% immunopositive cells was used for ER and PR positivity. Because we found that HRec status was an effect modifier (P<.007 for interaction; see Results), analyses were stratified for HRec status. Furthermore, because PFS can be influenced by consolidation endocrine therapy after taxane-based therapy, the analyses for PFS were repeated via exclusion of the patients treated with consolidation endocrine therapy and by censoring these patients at start of consolidation endocrine therapy. We also performed the analyses after excluding the 2 BRCA1-associated patients and the 4 sporadic patients who were treated with a taxane in combination with trastuzumab. Two sided P<.05 was considered statistically significant. All statistical analyses were performed with the use of SPSS version 15.0 software. RESULTS Patient and Tumor Characteristics Patient and tumor characteristics are presented in Table 1. The mean age at diagnosis of the primary breast cancer was 40 years, and the mean age at detection of metastatic disease was 43 years. Compared with sporadic tumors, BRCA1-associated tumors were significantly more often lymph node and HRec-negative. Furthermore, as expected, contralateral breast cancer was more often observed in BRCA-associated than in sporadic patients, reaching statistical significance regarding BRCA1-associated cases. The sites of first distant metastases and number of metastatic sites at detection were not significantly different between BRCA1-associated, BRCA2-associated, and sporadic patients. Taxane Chemotherapy Only a minority of patients (23% of BRCA1-associated patients, 16% of sporadic patients) were treated with a taxane as first-line therapy for metastatic disease (Table 2), whereas the majority (77% of BRCA1-associated patients, 100% of BRCA2-associated patients, 84% of sporadic patients) received docetaxel or paclitaxel as second- or third-line therapy. Furthermore, the majority of patients were treated with taxane monotherapy. Five patients (1 BRCA2-associated, 4 sporadic) initially treated with docetaxel switched to paclitaxel, and 1 sporadic patient receiving paclitaxel switched to docetaxel due to unacceptable toxicity. Two BRCA1-associated patients (1 HRec-positive and 1 HRec-negative breast cancer) were treated with the combination trastuzumab/taxane. They were matched with 4 sporadic patients also being treated with the combination taxane/trastuzumab. Nine Her-2/neu positive breast cancer patients (1 BRCA2-associated, 8 sporadic) did not receive trastuzumab in addition to taxane chemotherapy because they were treated before the era of trastuzumab as standard treatment for Her-2/neu positive disease. Three (9%) BRCA1-associated, 4 (31%) BRCA2-associated, and 17 (18%) sporadic patients received endocrine therapy after taxane chemotherapy as consolidation therapy. RRs and PFS BRCA1-associated patients had a worse response compared with sporadic and BRCA2-associated patients (both P<.001 for trend). Of the BRCA1-associated patients, 23% had an OR, compared with 84% and 38% of the BRCA2-associated and sporadic patients, respectively (Table 3). Furthermore, PD at first evaluation was Cancer February 15,

4 Table 1. Patient and Tumor Characteristics BRCA1- BRCA2- Sporadic No. of patients b Age at diagnosis of primary breast cancer, y Median Mean (SD) 39.8 (8.3) 40.9 (7.2) 40.2 (7.9) Range Year of diagnosis of primary breast cancer, no. (%) < (6) 2 (15) 11 (12) (31) 4 (31) 27 (28) (63) 7 (54) 57 (60) Age at diagnosis of metastatic breast cancer, y Median Mean (SD) 43.4 (8.5) 44.0 (7.4) 43.6 (7.8) Range Tumor size of primary tumor, no. (%) cm 15 (46) 3 (25) 36 (41) 2-5 cm 16 (48) 7 (58) 40 (45) >5 cm 2 (6) 2 (17) 12 (14) Unknown 2 ( ) 1 7 Nodal status, no. (%) Negative 17 (55) 6 (50) 25 (28) Positive 14 (45) 6 (50) 66 (72) Not done/unknown M status, no. (%) Negative 32 (91) 11 (85) 84 (88) Positive 3 (9) 2 (15) 11 (12) Histologic grade, no. (%) (0) 0 (0) 5 (7) 2 2 (8) 4 (57) 15 (22) 3 23 (92) 3 (43) 48 (71) Unknown 10 ( ) 6 ( ) 27 HRec status, no. (%) < Negative 20 (64) 1 (9) 19 (24) Positive 11 (36) 10 (91) 61 (76) Unknown Her-2/neu, no. (%) Negative 18 (89) 5 (83) 40 (77) Positive 2 (11) 1 (17) 12 (23) Unknown/not done Adjuvant chemotherapy, no. (%) No 22 (63) 9 (69) 54 (57) Anthracyclines 11 (31) 3 (23) 29 (30) CMF(-like) 2 (6) 1 (8) 9 (10) Other 0 (0) 0 (0) 3 (3) Adjuvant endocrine therapy, no. (%) No 30 (86) 10 (77) 77 (81) Yes 5 (14) 3 (23) 18 (19) Contralateral breast cancer, no. (%) No 26 (74) 10 (77) 88 (93) Yes 9 (26) 3 (23) 7 (7) Distant disease-free interval, no. (%) year 8 (23) 3 (23) 19 (20) (Continued) 902 Cancer February 15, 2012

5 Taxanes for BRCA1/2 Breast Cancer/Kriege et al Table 1. (Continued) BRCA1- BRCA2- Sporadic 1-2 years 7 (20) 3 (23) 18 (19) 2-5 years 13 (37) 5 (39) 36 (38) >5 years 7 (20) 2 (15) 22 (23) Site of first distant metastasis, no. (%) c Soft tissue 2 (6) 3 (23) 9 (10) Bone 6 (17) 3 (23) 25 (26) Visceral 27 (77) 7 (54) 61 (64) No. of sites of first metastasis, no. (%) One 16 (46) 5 (39) 48 (51) Multiple 19 (54) 8 (61) 47 (49) CMF, cyclophosphamide, methotrexate, fluorouracil; HRec, hormone receptor. Data are presented as no. (%) unless specified otherwise. a Versus sporadic patients. b One BRCA1 patient could only be matched with 1 sporadic breast cancer patient. c In case of multiple sites, the site with the worst prognosis was chosen (visceral>bone>soft tissue). Table 2. Patients Receiving Taxane Chemotherapy for Metastatic Breast Cancer BRCA1- BRCA2- Sporadic Line of chemotherapy, no. (%) First 8 b (23).54 0 ( ) (16) Second 19 (54) 9 (69) 61 (64) Third 8 (23) 4 (31) 19 (20) Type of taxane therapy, no. (%) Docetaxel 29 (83) (100) (80) Paclitaxel Weekly 0 ( ) 0 ( ) 6 (7) Thrice-weekly 2 (5) 0 ( ) 5 (5) Unknown 1 (3) 0 ( ) 2 (2) Combination with trastuzumab 2 (6) 0 ( ) 4 (4) Combination with other agents 1 (3) 0 ( ) 2 (2) Consolidation endocrine therapy after taxanes, no. (%) No 32 (91).28 9 (69) (82) Yes 3 (9) 4 (31) 17 (18) a Versus sporadic patients. b One BRCA1-associated patient treated with first-line taxane therapy was matched with only 1 sporadic patient. observed in the majority of BRCA1-associated patients (60%) in contrast with only 8% of BRCA2-associated and 19% of sporadic breast cancer patients. In addition, PFS was significantly shorter in BRCA1-associated patients (2.2 months) compared with BRCA2-associated (6.4 months, P ¼.02) and sporadic (4.9 months, P ¼.04) patients (Table 4). BRCA2-associated breast cancer patients had a significantly better RR than sporadic patients (P ¼.02 for trend) (Table 3), but the PFS was not significantly different between BRCA2-associated and sporadic patients (Table 4). For BRCA1-associated and sporadic patients, we found effect modification by HRec status (P ¼.007) (Table 5); therefore, analyses for RRs were performed in HRec-positive and -negative subgroups separately. In the subgroup of HRec-negative patients, significantly worse RRs were observed in BRCA1-associated compared with sporadic patients (OR, 20% vs 42%, and PD, 70% vs 26%, respectively; P ¼.03 for trend). On the other hand, in HRec-positive patients, RRs were not different between BRCA1-associated and sporadic breast cancer patients (OR, 36% vs 38%, PD, 28% vs 20%, respectively; P ¼.83 for trend). In addition, PFS was significantly Cancer February 15,

6 Table 3. Response Rates to Taxane Chemotherapy in All Patients, Stratified by Hormone Receptor Status BRCA1- P for BRCA 2- Trend a P for Trend a Sporadic All patients, no. (%) Objective response 8 (23) < (84) (38) Stable disease 6 (17) 1 (8) 40 (42) Progressive disease 21 (60) 1 (8) 18 (19) Unknown 1 1 HRec-negative, no. (%) Objective response 4 (20).03 0 (0) (42) Stable disease 2 (10) 1 (100) 6 (32) Progressive disease 14 (70) 0 (0) 5 (26) Unknown HRec-positive, no. (%) Objective response 4 (36).83 8 (89) (38) Stable disease 4 (36) 0 (0) 26 (42) Progressive disease 3 (28) 1 (11) 12 (20) Unknown 1 HRec, hormone receptor. a Versus sporadic patients. Table 4. Median Progression-Free Survival, Stratified by Hormone Receptor Status No. of Patients Median No. of Months (95% CI) All patients Sporadic ( ) BRCA1-associated ( ).04 BRCA2-associated ( ).17 HRec-negative Sporadic ( ) BRCA1-associated ( ).004 BRCA2-associated ( ).83 HRec-positive Sporadic ( ) BRCA1-associated ( ).26 BRCA2-associated ( ).19 CI, confidence interval; HRec, hormone receptor. a Versus sporadic patients (log-rank test). Table 5. Hazard Ratios for Risk of Progression After Taxane Chemotherapy No. of Patients HR (95% CI) HRec-negative patients Sporadic 19 1 ( ) BRCA1-associated ( ) BRCA2-associated 1 ( ) HRec-positive patients Sporadic 61 1 ( ) BRCA1-associated ( ) BRCA2-associated ( ) BRCA1-associated and sporadic patients Sporadic 80 1 ( ) BRCA1-associated ( ) HRec-positive 72 1 ( ) HRec-negative ( ) Genetic/HRec status a ( ) CI, confidence interval; HR, hazard ratio; HRec, hormone receptor. a Interaction between genetic status and HRec status (P ¼ 0.007). shorter in HRec-negative BRCA1-associated patients than in sporadic patients (median, 1.8 versus 3.8 months, respectively; P<.004) (Table 4 and Figure 1A), whereas among HRec-positive patients, PFS was similar in both groups (median, 5.7 months) (Table 4 and Figure 1B). In addition, univariate Cox proportional hazard analyses revealed significantly worse PFS in BRCA1-associated patients compared with sporadic patients in HRec-negative but not HRec-positive patients (Table 5). After adjusting for adjuvant chemotherapy and site of first distant relapse in a multivariate Cox analysis, the results remained similar and significant for the HRec-negative BRCA1-associated group (data not shown). Because only 1 BRCA2-associated patient had an HRec-negative tumor, we could not evaluate possible effect modification by HRec status for BRCA2 cases. HRec-positive BRCA2-associated patients had an OR significantly more often than sporadic patients (89% vs 38%; P ¼.03). No significant differences were observed between HRec-positive BRCA2-associated and sporadic patients regarding PFS (median, 7.1 and 5.7 months, respectively). 904 Cancer February 15, 2012

7 Taxanes for BRCA1/2 Breast Cancer/Kriege et al Figure 1. Progression-free survival is shown for BRCA1-associated, BRCA2-associated, and sporadic HRec-negative patients (A) and HRec-positive patients (B). Performing analyses for PFS after exclusion of patients treated with consolidation endocrine therapy and censoring these patients at the start of therapy did not alter the results (data not shown). Furthermore, performing all analyses after excluding the 2 BRCA1-associated patients and the 4 sporadic patients who were treated with a taxane in combination with trastuzumab showed similar results (data not shown). DISCUSSION To our knowledge, this is the first study of metastatic breast cancer patients to show that HRec-negative BRCA1-associated patients were significantly less sensitive to taxane chemotherapy compared with HRec-negative sporadic patients, not only in terms of a lower RR but also in terms of a shorter PFS. Among HRec-positive patients, no significant differences regarding taxane chemotherapy efficacy were observed between BRCA1-associated and sporadic patients. BRCA2-associated patients, primarily those with HRec-positive breast cancer, were found to be highly sensitive to taxane chemotherapy. Based on preclinical data, there is growing evidence that a functional BRCA1 protein is a necessary condition for the cytotoxic effect of taxanes. The present study confirms the preclinical data, however, only for BRCA1-associated patients with HRec-negative and not HRecpositive breast cancer. This finding might suggest that HRec-negative breast cancer (but not HRec-positive breast cancer) could be subdivided into 2 subgroups: with and without BRCA1 expression. This suggestion has been made by Rodriguez et al, 15 who reported that within triple-negative breast cancers, a defective DNA repair microarray gene expression pattern was associated with sensitivity to anthracyclines and resistance to taxane chemotherapy. However, a recent study observed that BRCA1 mutation carriers with triple-negative breast cancer had survival similar to that of noncarriers when treated with alkylating chemotherapy. 16 A plausible explanation for this finding is not yet known. Because the majority of BRCA1-associated breast cancers are HRec-negative (almost 80%), 17 one could speculate that HRec-positive breast cancers in BRCA1 mutation carriers are sporadic breast cancers (ie, they still have 1 functional BRCA1 allele left). However, this hypothesis has very recently been rejected by Tung et al, 18 who reported no difference in the prevalence of loss of wild-type BRCA1 between estrogen receptor positive and estrogen receptor negative BRCA1-associated breast cancers. In the current study, we observed that BRCA2-associated patients (mostly HRec-positive) were highly sensitive to taxane chemotherapy in terms of a significantly higher RR and a not significantly different PFS compared with sporadic patients. Despite the small numbers, the findings are interesting, especially because our data extend on the very scarce available data hereon. To our knowledge, only 1 previous study suggested an inverse relationship between BRCA2 expression and sensitivity to taxane chemotherapy. 13 In that small study (n ¼ 25), it was observed that breast cancers with a low BRCA2 mrna level had a higher response to taxane chemotherapy compared with breast cancers with a high BRCA2 mrna level. Although concordant with our findings, more studies including larger numbers of BRCA2-positive breast cancer patients are warranted. Despite the unique and interesting results, this study has several limitations. First, it had a retrospective design, and consequently patients were treated with various Cancer February 15,

8 taxanes and/or schemes. It is known that paclitaxel given in a weekly scheme is more effective than when administered in a thrice-weekly scheme. 19 However, because only a very limited number of patients (2 BRCA1-associated [5%] and 5 sporadic [5%]) received paclitaxel in a thriceweekly scheme, we anticipate that this does not have a major impact on the results. Furthermore, compared with previously published data on the efficacy of taxanes, our sporadic patients showed comparable RRs (38% vs 35%-60%) and median PFS (4.9 vs months). 3 This indicates that we constructed a representative patient group. Second, the Her- 2/neu status is unknown in a large portion of the patients. However, despite being a marker of adverse prognosis among patients not treated with trastuzumab, there are no reasons to suggest that the efficacy of taxane chemotherapy differs among Her-2/neu positive and Her-2/neu negative breast cancer patients. Also, because combination treatment taxane/trastuzumab leads to a longer PFS, it is reassuring that repeating the analyses excluding the patients receiving trastuzumab did not alter our results. A third shortcoming is that PFS could have been influenced by consolidation endocrine therapy after taxane chemotherapy, which was given to 3 BRCA1-associated patients, 4 BRCA2-associated patients, and 17 sporadic patients. As mentioned in the Results, performing analyses for PFS by excluding patients treated with consolidation endocrine therapy and censoring these patients by date of start of therapy showed similar results, leaving the conclusions unaltered (data not shown). Evidence is growing that various biomarkers could be a marker for response to different chemotherapeutic agents, as could BRCA deficiency. It has been reported that BRCA1- and BRCA2-associated breast cancer patients have an increased sensitivity to anthracyclines, platinum, and poly(adenosine diphosphate ribose) polymerase inhibitors The findings of the current study provide data on a reduced efficacy of taxane chemotherapy in HRec-negative BRCA1-associated patients compared with sporadic breast cancer patients. Whether HRec status also plays a role in the sensitivity to other cytotoxic agents within the BRCA1-associated group has not been investigated yet. From a clinical point of view, however, the data presented here could be of great importance. If confirmed, this might already have implications regarding the choice of (adjuvant) systemic chemotherapy. Therefore, larger and prospective studies are eagerly needed to confirm our results. Meanwhile, it seems justified to treat patients with metastatic BRCA1-associated breast cancer with anthracycline- or platinum-containing agents before treating them with a taxane, especially in the case of negative HRecs. Also, it becomes more and more relevant to perform genetic testing for a BRCA mutation at breast cancer diagnosis, especially in young (<50 years) triple-negative cases, because therapy choice may depend on the knowledge of a functional BRCA1 pathway in triple-negative breast cancer. In conclusion, the current analyses showed a reduced sensitivity to taxane chemotherapy in HRec-negative BRCA1-associated metastatic breast cancer patients compared with age-matched, HRec-negative sporadic patients. Taxane chemotherapy was similarly effective in hormone-sensitive, BRCA1-associated patients compared with sporadic patients. Larger prospective studies are eagerly needed, because the findings could have a major impact on the choice of the type of (adjuvant) chemotherapy for BRCA mutation carriers. Likewise, clinicians should address genetic testing, especially in triple-negative breast cancer at young age, at the diagnosis of breast cancer. FUNDING SOURCES Supported by Grant DDHK from the Dutch Cancer Society. CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures. REFERENCES 1. Early breast cancer trialists collaborative group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365: De Laurentiis M, Cancello G, D Agostino D, et al. Taxanebased combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials. J Clin Oncol. 2008;26: Saloustros E, Mavroudis D, Georgoulias V. Paclitaxel and docetaxel in the treatment of breast cancer. Expert Opin Pharmacother. 2008;9: Lafarge S, Sylvain V, Ferrara M, et al. Inhibition of BRCA1 leads to increased chemoresistance to microtubule-interfering agents, an effect that involves the JNK pathway. Oncogene. 2001;20: Quinn JE, Kennedy RD, Mullan PB, et al. BRCA1 functions as a differential modulator of chemotherapy-induced apoptosis. Cancer Res. 2003;63: Tassone P, Tagliaferri P, Perricelli A, et al. BRCA1 expression modulates chemosensitivity of BRCA1-defective HCC1937 human breast cancer cells. Br J Cancer. 2003;88: Cancer February 15, 2012

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