A new paradox for pCR in BRCA mutation carriers

A new paradox for pCR in BRCA mutation carriers

Konstantinos Rounis, Dimitrios Mavroudis

Department of Medical Oncology, University Hospital of Heraklion, Crete, Greece

Correspondence to: Dimitrios Mavroudis. Medical Oncology Medical School, University of Crete, Crete, Greece. Email: mavrudis@med.uoc.gr.

Comment on: Fasching PA, Loibl S, Hu C, et al. BRCA1/2 Mutations and Bevacizumab in the Neoadjuvant Treatment of Breast Cancer: Response and Prognosis Results in Patients With Triple-Negative Breast Cancer From the GeparQuinto Study. J Clin Oncol 2018;36:2281-7.

Submitted Oct 16, 2018. Accepted for publication Oct 29, 2018.

doi: 10.21037/tcr.2018.10.25

Pathologic complete response (pCR) in neoadjuvant chemotherapy (NACT) in breast cancer and especially in the triple negative subtype (TNBC) is considered an important surrogate end point for disease free survival (DFS), event free survival (EFS) and overall survival (OS) (1). Breast tumors of patients carrying a germline BRCA1/2 mutation represent a subgroup with unique biological characteristics (2). A subgroup analysis of the previously reported GeparQuinto study (3) was recently published by Fasching et al. in the Journal of Clinical Oncology (4) of the TNBC patients who carried a germline BRCA1/2 mutation, and found that the addition of bevacizumab to the NACT regimen of anthracycline/cyclophosphamide followed by weekly paclitaxel, significantly increased pCR rates (ypT0/is-ypN0) to 61.5% vs. 41.2% in the non-bevacizumab arm. However, this increase in pCR was not translated into an improved DFS (HR, 0.74; 95% CI, 0.32–1.69; P=0.472) (4).

So far, the clinical trials that have studied the addition of bevacizumab to NACT in breast cancer have yielded conflicting results. GeparQuinto and CALGB 40603 showed that the addition of bevacizumab in the neoadjuvant setting of HER-2 negative and triple negative breast cancer patients, respectively, produced an increased rate of pCR of about 10% (3,5). The effect from the addition of bevacizumab in the GeparQuinto study was more pronounced in the triple negative subgroup. The updated results of CALGB 40603 presented at the 2015 San Antonio Breast Cancer Symposium showed that despite the fact that the patients who achieved pCR had improved RFS and OS, these clinical benefits lacked a significant association with the addition of bevacizumab, thus rendering the study underpowered (6). In the NSABP B40 study the addition of bevacizumab to a NACT regimen consisting of docetaxel/doxorubicin and capecitabine or gemcitabine (depending on the study arm) showed benefit for pCR and OS only in women with hormone receptor–positive disease, with negative findings in the TNBC subgroup (7,8). The ARTemis study randomized women with HER2-negative breast cancer receiving NACT with 3 cycles of docetaxel followed by 3 cycles of cyclophosphamide, epirubicin, and fluorouracil, with or without bevacizumab. Initially, the patients of the bevacizumab arm had increased rates of pCR, an effect that was more pronounced in the TNBC subgroup (45% vs. 31%) (9). However, after 3.5 years of follow up, there was no clear benefit in terms of PFS and OS in the cohort of patients who received bevacizumab although pCR in the non-bevacizumab group was associated with an increased PFS and OS (10). These results were explained by the researchers with the hypothesis that micrometastatic breast cancer may grow in an angiogenesis-independent manner. In the GeparSixto trial 595 patients with TNBC were randomized into 2 groups, with both groups receiving 18 weeks of weekly paclitaxel in combination with weekly non-pegylated liposomal doxorubicin, and bevacizumab every 3 weeks. The experimental arm additionally received weekly carboplatin. A total of 333 women completed treatment in the both arms. The addition of carboplatin resulted in a significantly improved pCR rate over control (53% vs. 37%; P=0.005). This increase in pCR was translated into an absolute benefit in 3-year EFS for the addition of carboplatin over control of 9.7% [85.8% vs. 76.1%, respectively; HR, 0.56 (95% CI, 0.33–0.96)]. Due to the addition of carboplatin it is not feasible to determine any possible benefit from the addition of bevacizumab (11). Summarizing all the previous data, there is no clear and proven clinical benefit from the addition of bevacizumab in TNBC in the neoadjuvant setting.

In the GeparQuinto study, 1,984 patients with HER-2 negative breast cancer were initially enrolled and 678 of them had TNBC. Genotype data were obtained for 493 patients. Amongst them 90 patients had germline mutations in BRCA1/2 genes, 74 in the BRCA1 gene and 16 in the BRCA2 gene. Fifty-one BRCA mutation carriers were randomized in the non-bevacizumab arm (40 had BRCA1 mutation and 11 BRCA2 mutation) and 39 mutation carriers were randomized in the bevacizumab arm (34 with BRCA1 mutation and 5 with BRCA2 mutation). In the TNBC subgroup of the study, the BRCA1/2 mutations carriers had increased rates of pCR compared to non-carriers 50% vs. 31.5% irrespectively of the administration of bevacizumab [odds ratio (OR), 2.17; 95% CI, 1.37–3.46; P=0.001]. The pCR rates were similar for BRCA1 (48.6%) and BRCA2 (56.3%) mutation carriers. BRCA1/2 mutations carriers had a significantly improved DFS (HR, 0.644; 95% CI, 0.415–0.998; P=0.047) than those with no mutations. The addition of bevacizumab in BRCA mutation carriers lead to pCR in 61.5% of them vs. 41.2% for the BRCA mutation carriers that were randomized in the non-bevacizumab arm. Interestingly enough though, the increased pCR rate in patients with BRCA1/2 mutations was not significantly associated with an improved DFS (HR, 0.74; 95% CI, 0.32–1.69; P=0.472). Due to the increased risk of this specific patient population for contralateral breast cancer development the researchers analyzed the data also with distant DFS (DDFS) as the outcome variable and the analysis yielded similar results. As expected, the patients without BRCA1/2 mutations derived substantial benefit from pCR (HR, 0.18; 95% CI, 0.11–0.31; P<0.001) (4).

Although we must interpret with caution the results of the GeparQuinto study due to the small number of patients enrolled who had BRCA1/2 mutations and especially the very few patients harboring BRCA2 mutations, it seems that the addition of bevacizumab in the NACT regimen in BRCA mutation carriers increases the pCR rate. This effect was explained by the researchers due to the synthetic lethality phenomenon caused by angiogenesis inhibition and the lack of a functional homologous recombination machinery in BRCA mutant cells (12). In addition, BRCA mutation carriers had a higher pCR rate compared with non-carriers regardless of bevacizumab administration and improved DFS. However, TNBC BRCA mutation carriers do not seem to have a better prognosis than the non-carriers based on the largest prospective cohort study conducted so far by Copson et al. (13).

Is pCR a surrogate marker for better clinical outcome for BRCA mutation carriers? Paluch-Shimon et al. in a single institution prospective study using a smaller number of patients (34 BRCA mutation carriers) who received neoadjuvant therapy with dose dense doxorubicin/cyclophosphamide followed by paclitaxel found no difference in relapse-free survival regardless of pCR status (log-rank P=0.25). In contrast, in the non-carrier cohort, the achievement of pCR seemed to retain its expected prognostic significance (log-rank P=0.0001) (14). The results of this study are in concordance with the results of GeparQuinto as they both demonstrate lack of prognostic value for pCR in BRCA mutation carriers. On the contrary in the GeparSixto trial, the data did not show a differential effect of pCR in the prognosis of patients with and without BRCA1/2 mutation. However, the number of BRCA mutation carriers was small (n=50) and due to the effect of carboplatin the possible beneficial role in EFS from the addition of bevacizumab remains uncertain.

Is there an explanation for the results of GeparQuinto? The increased pCR rates in BRCA mutation carriers irrespectively from the addition of bevacizumab can be attributed to the unique biologic characteristics conferred to the tumor by the lack of a functional BRCA1/2 gene. The increased capacity of chemotherapy with anthracycline/taxane/cyclophosphamide combination to induce pCR in BRCA mutant tumors was also shown by Paluch-Shimon et al. (14). BRCA mutation carriers have an intrinsic defect in homologous DNA recombination. This defect possibly confers greater chemosensitivity to treatments with DNA damage inducing agents such as anthracyclines and cyclophosphamide (15). More importantly however, is to explain the lack of correlation between pCR after NACT for BRCA1/2 mutation carriers and an improved prognosis. We can postulate that the answer lies in the unique genetic characteristics of the tumors that bear mutations in the BRCA genes and how these affect the interaction of the malignant cells with the host’s immune system. The defect in homologous recombination may increase tumor neoantigen load due to the inability of these cells to correct the DNA damage properly. Lin studied tumors from 82 patients with early onset breast cancer and found using whole exome sequencing that tumors with mutations in the genes that control homologous recombination or MMR have higher number of neopeptides with high binding affinity and immunogenicity than wild type tumors (16). Moreover, possibly due to the increased neoantigen load these tumors have been associated in some studies with increased number of tumor infiltrating lymphocytes (17). The higher immunogenicity of these tumors may lead to a more effective immunosurveillance by the host’s immune system in the setting of micrometastatic disease thus obscuring the possible beneficial effect of a pCR after NACT on patients’ clinical outcome.

In conclusion the role of bevacizumab in NACT for BRCA mutation carriers remains controversial because although it seems to increase pCR rates, it does not improve clinical outcome for these patients. In the era of immune checkpoint inhibitors and PARP inhibitors and the promising results of the addition of these agents in the neoadjuvant setting (18,19) it may be difficult for bevacizumab to find its place. This study showed us a new paradox for the achievement of pCR in a patient who carries a BRCA mutation since the implication on prognosis was not what we would have expected.


Funding: None.


Provenance and Peer Review: This article was commissioned and reviewed by the Section Editor San-Gang Wu (Department of Radiation Oncology, Xiamen Cancer Center, the First Affiliated Hospital of Xiamen University, Xiamen, China).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2018.10.25). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.


  1. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014;384:164-72. [Crossref] [PubMed]
  2. Stoppa-Lyonnet D. The biological effects and clinical implications of BRCA mutations: where do we go from here? Eur J Hum Genet 2016;24:S3-9. [Crossref] [PubMed]
  3. von Minckwitz G, Eidtmann H, Rezai M, et al. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med 2012;366:299-309. [Crossref] [PubMed]
  4. Fasching PA, Loibl S, Hu C, et al. BRCA1/2 Mutations and Bevacizumab in the Neoadjuvant Treatment of Breast Cancer: Response and Prognosis Results in Patients With Triple-Negative Breast Cancer From the GeparQuinto Study. J Clin Oncol 2018;36:2281-7. [Crossref] [PubMed]
  5. Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol 2015;33:13-21. [Crossref] [PubMed]
  6. WM Sikov, DA Berry, CM Perou, et al. Abstract S2-05: Event-free and overall survival following neoadjuvant weekly paclitaxel and dose-dense AC +/- carboplatin and/or bevacizumab in triple-negative breast cancer: Outcomes from CALGB 40603 (Alliance). Cancer Res 2016;76:Abstract nr S2-05.
  7. Bear HD, Tang G, Rastogi P, et al. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med 2012;366:310-20. [Crossref] [PubMed]
  8. Bear HD, Tang G, Rastogi P, et al. Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial. Lancet Oncol 2015;16:1037-48. [Crossref] [PubMed]
  9. Earl HM, Hiller L, Dunn JA, et al. Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide, for women with HER2-negative early breast cancer (ARTemis): an open-label, randomised, phase 3 trial. Lancet Oncol 2015;16:656-66. [Crossref] [PubMed]
  10. Earl HM, Hiller L, Dunn J, et al. Disease-free (DFS) and overall survival (OS) at 3.4 years (yrs) for neoadjuvant bevacizumab (Bev) added to docetaxel followed by fluorouracil, epirubicin and cyclophosphamide (D-FEC), for women with HER2 negative early breast cancer: The ARTemis trial. J Clin Oncol 2016;34:1014. [Crossref]
  11. von Minckwitz G, Schneeweiss A, Loibl S, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol 2014;15:747-56. [Crossref] [PubMed]
  12. Bindra RS, Schaffer PJ, Meng A, et al. Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cells. Mol Cell Biol 2004;24:8504-18. [Crossref] [PubMed]
  13. Copson ER, Maishman TC, Tapper WJ, et al. Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study. Lancet Oncol 2018;19:169-80. [Crossref] [PubMed]
  14. Paluch-Shimon S, Friedman E, Berger R, et al. Neo-adjuvant doxorubicin and cyclophosphamide followed by paclitaxel in triple-negative breast cancer among BRCA1 mutation carriers and non-carriers. Breast Cancer Res Treat 2016;157:157-65. [Crossref] [PubMed]
  15. Yang F, Teves SS, Kemp CJ, et al. Doxorubicin, DNA torsion, and chromatin dynamics. Biochim Biophys Acta 2014;1845:84-9. [PubMed]
  16. Lin PH. Association of DNA repair gene-mutation, mutation burden and, neoantigen load in breast cancer. J Clin Oncol 2018;36:9. [Crossref]
  17. Force JM, Abbott S, Broadwater G, et al. Immune profiling of BRCA-mutated breast cancers. J Clin Oncol 2018;36:abstr 585.
  18. Rugo HS, Olopade O, DeMichele A, et al. Abstract S5-02: Veliparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer: First efficacy results from the I-SPY 2 TRIAL. Cancer Res 2013;73:S5-02-S5-02.
  19. Nanda R, Liu MC, Yau C, et al. Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): Results from I-SPY 2. J Clin Oncol 2017;35:abstr 506.
Cite this article as: Rounis K, Mavroudis D. A new paradox for pCR in BRCA mutation carriers. Transl Cancer Res 2019;8(Suppl 2):S99-S102. doi: 10.21037/tcr.2018.10.25

Download Citation