Reply to S. Takamizawa et al

In their correspondence, Takamizawa et al¹ propose potential reasons why the pathologic complete response (pCR) rate to cisplatin (CDDP) is lower than estimated in the INFORM study (ClinicalTrials.gov identifier: NCT01670500) and question whether an amendment affected the reliability of the study.

As the authors mention, the initial report by Byrski et al² that cites an 83% pCR rate to CDDP was based on only 12 gBRCA1 mutation carriers with triple-negative breast cancer (TNBC). In their final report, Byrski et al³ observed similar pCR rates for CDDP among BRCA carriers with TNBC (52 [61%] of 86) or estrogen receptor (ER)–positive disease (9 [56%] of 16). Like Takamizawa et al,¹ we had been concerned that the inclusion of BRCA carriers with ER-positive disease might lower the pCR rate with CDDP in the INFORM trial and chose a conservative pCR rate of 50% with CDDP to power our study. We did observe a lower pCR rate with ER-positive disease (14%) than with TNBC (26%) for both treatment arms combined, and especially with CDDP (6% for ER positive and 23% for TNBC),⁴ although we caution that sample sizes are small. Rates for pCR or residual cancer burden 1 for both treatments combined were 34% for ER-positive tumors and 41% for TNBC, and with CDDP 25% (ER positive) and 36% (TNBC). Other data for response to single-agent platinum therapy in BRCA carriers with ER-positive disease are scarce. In the TNT trial, carriers with metastatic breast cancer had a significantly higher response rate with carboplatin than with docetaxel; however, only 11 BRCA carriers with ER-positive disease were enrolled and responses were not reported by breast cancer subtype.⁵

The INFORM trial found that the pCR rate for TNBC was 29% with AC and 23% with CDDP. Therefore, whereas the pCR rate with CDDP may have been lower as a result of the inclusion of BRCA carriers with ER-positive disease, it is extremely unlikely that CDDP would have been superior to AC had the study enrolled only carriers with TNBC.

Takamizawa et al¹ also suggest that the inclusion of BRCA2 carriers may have lowered the pCR rate with CDDP. It is difficult to separate BRCA2 status from hormone receptor status since the majority of BRCA2-associated breast cancers are ER positive.⁶ In our study, 66% of BRCA2 carriers had ER-positive disease. The pCR rate with CDDP was 20% among BRCA1 carriers and 13% for BRCA2 carriers. Data for response to platinum monotherapy among BRCA2 carriers are limited, with only two BRCA2 carriers included in the TBCRC 009 study.⁷ Given that there were only 12 BRCA2 carriers in the TNT trial—9 patients received carboplatin—those investigators concluded that it would not be meaningful to assess an interaction between treatment effect and the BRCA gene.⁵

Takamizawa et al¹ also hypothesize that less CDDP drug delivered than doxorubicin and cyclophosphamide may have contributed to the lower pCR rate with CDDP. Although there were a few more dose delays and reductions with CDDP—largely from nausea, vomiting, and acute renal injury—these differences were small and unlikely to affect the results. Indeed, these data serve as a reminder that CDDP can be associated with significant toxicities. Tolerability of a particular chemotherapy regimen certainly can contribute to the effectiveness of that regimen.

Finally, Takamizawa et al¹ question whether an amendment extending enrollment to those with tumors > 1 cm—initial criterion was tumors > 1.5 cm—or to those who had received prior chemotherapy may have decreased the reliability of the study. Twenty of the 117 patients in our study were enrolled after the amendment, only one had T < 1.5 cN0, and none received prior chemotherapy. Thus, although this amendment could have limited the generalizability of the results, that was not the case in our study.

We recognize that platinum agents are effective in the treatment of breast cancer in BRCA carriers and are more active in carriers with TNBC than noncarriers.^5,6,8 We share the disappointment of Takamizawa et al that CDDP did not perform better. However, the objective of the INFORM trial was to compare pCR rates with CDDP and AC in BRCA carriers with breast cancer. Our study did not show a superior pCR rate with CDDP and suggests that observed responses are likely a result of DNA-damaging chemotherapy in general and not platinum specifically.

With regard to future phase III trials, we await the results of ongoing (neo)adjuvant trials using poly (ADP-ribose) polymerase inhibitors in BRCA carriers with early-stage breast cancer—for example, ClinicalTrials.gov identifiers: NCT02032823 and NCT03499353. If these trials show a significant benefit for poly (ADP-ribose) polymerase inhibitors, it will be important to determine how best to use these agents and chemotherapy in randomized trials.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Reply to S. Takamizawa et al

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

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Nadine Tung

Research Funding: AstraZeneca, Myriad Genetics (Inst)

Judy E. Garber

Consulting or Advisory Role: Novartis (I), GTx (I), Helix BioPharma, Konica Minolta, Aleta BioTherapeutics (I), H3 Biomedicine (I), Kronos Bio (I)

Research Funding: Novartis (I), Ambry Genetics, Invitae Genetics, Myriad Genetics

Other Relationship: Susan G. Komen for the Cure (I), American Association for Cancer Research, Diane Helis Henry Medical Foundation (I), James P. Wilmot Foundation (I), Adrienne Helis Malvin Medical Research Foundation (I), Breast Cancer Research Foundation, Facing our Risk of Cancer Empowered

No other potential conflicts of interest were reported.