Pathological response and survival in triple-negative breast cancer following neoadjuvant carboplatin plus docetaxel

Abstract

Purpose:

Prognostic value of pCR and extent of pathological response attained with anthracycline-free platinum plus taxane neoadjuvant chemotherapy (NAC) in TNBC is unknown. We report recurrence-free survival (RFS) and overall survival (OS) according to degree of pathological response in patients treated with carboplatin (Cb) plus docetaxel (D) NAC.

Experimental Design:

190 patients with stage I-III TNBC were treated with neoadjuvant Cb(AUC6) plus D(75mg/m²) every 21 days x 6 cycles. pCR (no evidence of invasive tumor in breast and axilla) and Residual Cancer Burden (RCB) were evaluated. Patients were followed for recurrence and survival. Extent of pathological response was associated with RFS and OS using the Kaplan-Meier method.

Results:

Median age was 51 years, and 52% were node-positive. pCR and RCB I rates were 55% and 13%, respectively. 5% of pCR patients, 0% of RCB I patients, and 58% of RCB II/III patients received adjuvant anthracyclines. Three-year RFS and OS were 79% and 87%, respectively. Three-year RFS was 90% in patients with pCR and 66% in those without pCR (HR=0.30; 95% CI: 0.14–0.62, P=0.0001). 3-year OS was 94% in patients with pCR and 79% in those without pCR (HR=0.25; 95% CI: 0.10–0.63, P=0.001). Patients with RCB I demonstrated 3-year RFS (93%) and OS (100%) similar to those with pCR. On multivariable analysis, higher tumor stage, node positivity, and RCB II/III were associated with worse RFS.

Conclusions:

Neoadjuvant CbD yields encouraging efficacy in TNBC. Patients achieving pCR or RCB I with this regimen demonstrate excellent 3-year RFS and OS without adjuvant anthracycline.

ClinicalTrials.gov: NCT02302742, NCT01560663

Introduction

Triple-negative breast cancer (TNBC), which is defined by the lack of expression of estrogen receptor (ER), progesterone receptor (PgR), and absence of ERBB2 (HER2) overexpression and/or gene amplification, accounts for 15% of all breast cancers in the United States. Compared to other breast cancer subtypes, TNBC is associated with inferior long-term outcomes (1–3). Adjuvant chemotherapy reduces the risk of distant recurrence and death in patients with TNBC and is generally recommended for TNBC patients with stage I (T>1cm)–III disease (4–6). Even so, despite receiving standard anthracycline-taxane-based chemotherapy, a significant proportion (20–40%) of patients with early-stage TNBC develop metastatic disease (7, 8). Improved therapeutic approaches are thus desired for TNBC. In the absence of available actionable molecular targets, modifications of traditional chemotherapy regimens (i.e., the addition of platinum agents) may be potential means of improving outcomes for this breast cancer subtype.

Platinum compounds generate double-stranded DNA breaks that are preferentially repaired by the mechanism of homologous recombination. Phenotypic and molecular similarities between BRCA-associated and sporadic TNBC suggest that homologous recombination deficiency may be a shared alteration that can be targeted in a larger subset of TNBC (7, 9–13). Germline BRCA1/2 mutations are the prototype molecular alterations that confer homologous recombination deficiency and sensitivity to DNA-damaging therapy. Only 15–20% of patients with TNBC harbor germline BRCA mutations; however, additional mechanisms such as promoter methylation, transcript instability/attenuation, or somatic/germline mutations in other homologous recombination pathway genes may compromise DNA repair machinery (14–17). It has recently been reported that comprehensive evaluation of factors beyond germline BRCA mutation reveals homologous recombination deficiency in 50–60% of TNBC, expanding the therapeutic potential of DNA-damaging agents like platinum compounds within the general population of TNBC (16, 18). Neoadjuvant studies demonstrate that addition of carboplatin to anthracycline and taxane-based neoadjuvant chemotherapy (NAC) improves pathological complete response (pCR) in TNBC (11, 19–22). However, the improvement in pCR rate comes at the cost of increased toxicity (11, 19, 21, 22). Exploration of a platinum-based chemotherapy regimen with an improved toxicity profile in TNBC is therefore warranted. Taxanes demonstrate significant activity in TNBC as well as preclinical and clinical synergy with platinum agents, providing rationale for evaluation of a platinum-taxane combination in TNBC (23–28).

We have recently reported encouraging efficacy of a carboplatin (Cb) plus docetaxel (D) NAC regimen in TNBC (29). In this study, overall pathological complete response (pCR) rates were 55% and were not influenced by germline BRCA mutation status (pCR 59% in BRCA-associated TNBC, 56% in BRCA wild-type TNBC). Here we report 3-year recurrence-free and overall survival from the same study population. We also present the correlation between survival outcomes and degree of pathological response as assessed by residual cancer burden (RCB).

Patients and Methods

Patient Population

The study population includes patients with stage I–III TNBC treated with a NAC regimen of CbD in two separate and independent prospective cohorts. Details of the study population have been previously published (29). A brief description of the study population is provided below.

University of Kansas (KU) cohort: Patients with stage I (T≥1 cm), II, and III TNBC were enrolled in an IRB-approved multisite prospective registry protocol (NCT02302742). Triple negativity was defined as estrogen receptor (ER) and progesterone receptor (PgR) immunohistochemical (IHC) nuclear staining of less than 10% and HER2 IHC staining of 0 to 1+ or fluorescence in situ hybridization (FISH) ratio <2.0 if IHC 2+ or if IHC not performed (30). From 2011 to 2015, 69 enrolled patients with stage I (T>1cm), II, and III TNBC were treated with a NAC regimen of CbD.

MMJ-CAR-2014–01 (Spanish) cohort: Female patients with pathologically confirmed diagnosis of stage II–III (T≥2cm) TNBC were enrolled on a prospective, multicenter, non-randomized trial exploring the antitumor activity of neoadjuvant CbD (NCT01560663). See supplemental material for list of participating institutions. Triple negativity was defined as ER and PgR nuclear staining of less than 1% by IHC and HER2 IHC staining of 0 to 1+ or FISH ratio <2.0 if IHC 2+ or if IHC not performed (30). Between 2010 and 2015, 123 patients with stage II and III TNBC were enrolled and treated with neoadjuvant CbD.

This study was conducted in accordance with the U.S. Common Rule and the International Ethical Guidelines for Biomedical Research Involving Human Subjects. Human investigations were performed after approval by the institutional review board at each institution, and all subjects provided written informed consent.

Study Procedures

As previously described (29), patients in both cohorts were prescribed a NAC regimen of carboplatin (AUC 6) + docetaxel (75 mg/m²) given every 21 days for 6 cycles. All patients received myeloid growth factor support (KU cohort: 6 mg pegfilgrastim on D2, Spanish cohort: filgastrim 300 μg/day x 5–7 days after chemotherapy, according to the guidelines of each institution). In patients with clinically suspicious axillary lymph node/s, histological confirmation by biopsy or fine-needle aspiration was encouraged. Following NAC, all patients underwent breast surgery. Axillary sampling was required except in patients with pretreatment negative sentinel lymph nodes. Twenty-two percent (41/183) of the per-protocol population underwent pretreatment sentinel lymph node biopsy; completion dissection was required in case of positive pretreatment sentinel lymph node biopsy (additional information regarding pretreatment axillary lymph node assessment is included as supplemental text). Extent of axillary surgery, subsequent irradiation, and postoperative adjuvant chemotherapy were otherwise determined by the treating physician. Patients were prospectively followed for recurrence and survival status.

Pathologic Evaluation

As previously described (29), pathologic response was determined locally without central pathologic review. All surgical pathology reports were centrally reviewed by the principal investigators of the respective cohorts. pCR was defined as the absence of residual invasive disease in the breast and axilla with or without ductal carcinoma in situ (ypT0/isN0). Patients with pCR in the breast and negative pretreatment sentinel lymph nodes were considered to have achieved pCR. Residual cancer burden (RCB) for all patients was calculated centrally (utilizing parameters reported on individual patient pathology reports), blinded to enrollment site, using the classification by Symmans et al (31). Patients achieving pCR (RCB 0) or near-pCR (RCB I) were assessed within the group RCB 0/I.

Germline BRCA1/2 Testing

KU cohort:

Germline testing for BRCA1/2 was done utilizing commercially available tests and laboratories.

Spanish cohort:

Germline testing for BRCA1/2 was done at Sistemas Genómicos facilities using targeted next-generation sequencing of 7 genes (BRCA1, BRCA2, PALB2, BARD1, RAD50, RAD51C, RAD51D) and multiplex ligation-dependent probe amplification (MLPA) by quantification of probes corresponding to BRCA1 and BRCA2 genes using the MLPA kit (MRC-Holland, Amsterdam, Netherlands) according to the manufacturer’s recommendations, fragment analysis by ABI 3730xl genetic analyzer (Applied Biosystems, Foster City, CA), and data normalization and interpretation of results using Coffalyser.net software as recommended by MRC-Holland. Only BRCA1 and BRCA2 results are available and reported for this analysis.

Patients with germline BRCA1 or BRCA2 mutation were counseled in both cohorts as per institutional guidelines.

Statistical Methods

Relevant demographic, treatment, and outcome variables of the Spanish and KU cohorts were combined for analysis. Demographic and toxicity data depict the intent-to-treat population, while all other analyses reflect the per-protocol patient population. Recurrence-free survival (RFS) was defined as the time from diagnosis to first recurrence (invasive ipsilateral breast, invasive local/regional, or distant) or to death as a result of any cause (32). Overall survival (OS) was defined as time from diagnosis to death as a result of any cause. Patients were censored on the date of last contact if an event had not been observed. Confidence intervals (CIs) for the proportion of patients with pCR and RCB 0/I were calculated according to the exact two-sided binomial test. Survival curves were assessed by the Kaplan-Meier method, and unadjusted survival comparisons were conducted using log-rank tests. Cox regression modeling was used for univariate and multivariable analysis of factors associated with risk of recurrence and death. All reported P-values and CIs are from two-sided tests. All analyses were conducted using SPSS Statistics version 22 (IBM Corporation, Armonk, NY).

Results

Study Cohort

A CONSORT diagram depicting cohort identification has been provided (figure 1). As previously reported (29), the study population included 190 subjects treated in KU and Spanish cohorts between 2010 and 2015. Two patients were found to have metastatic disease after enrollment and were excluded from the intent-to-treat population. Seven patients in the intent-to-treat population were not included in the per-protocol analysis (consent withdrawn or lost to follow-up prior to definitive breast surgery).

Figure 1:

CONSORT diagram

^a In addition to the various centers in Spain, the Spanish cohort includes a center from Lima, Peru.

Patient Characteristics

Table 1 describes the demographic and baseline clinical characteristics of the study population. For the overall study population, median age was 51 years (range: 29–81 years), 14% were Hispanic, 7% were black, and 52% had clinically node-positive disease. Sixteen percent of the study population carried a deleterious BRCA1/2 mutation (germline BRCA testing results were available for 87% of patients). A small percentage (3%, all from KU cohort) had ER/PgR expression between 1% and 10%.

Table 1:

Patient Characteristics

	All Patients (N=190)
Age at Diagnosis, years – Median (Range)	51 (29–81)
Race – N (%)
Caucasian	174 (92%)
Black	14 (7%)
Asian	2 (1%)
Ethnicitya
Hispanic	26 (14%)
Non-Hispanic	163 (86%)
Menopausal status
Pre/peri	86 (45%)
Post	98 (52%)
Unknown	6 (3%)
Histological grade
1	1 (1%)
2	39 (21%)
3	140 (78%)
T stage
1	23 (12%)
2	104 (55%)
3	34 (18%)
4	29 (15%)
Lymph node status
Negative	90 (47%)
Positive	98 (52%)
Unknown	2 (1%)
ER/PR IHC
0%	184 (97%)
1–10%	6 (3%)
Germline BRCA mutation
Absent	136 (71%)
Present	30 (16%)
Unknown	24 (13%)
Surgery typeb
Lumpectomy	84 (45%)
Mastectomy	101 (55%)
pCR (N=183) b
Yes	100 (55%)
No	83 (45%)
RCB 0/I (N=180)c
Yes	123 (68%)
No	57 (31%)
Adjuvant chemotherapy in patients with RCB II+III (N=57)
Yes	33 (58%)
No	24 (42%)

^aEthnicity is not known for one patient

^bSurgical information is not available for five patients

^cRCB status is not available for three patients

Pathological Response

Pathological complete response and RCB I for the per-protocol study population (N=183) were 55% (100/183) (95% CI: 48%–62%) and 13% (23/183) (95% CI: 8%–18%), respectively (supplemental figure 1), as previously reported (29). Taken together, this yields a RCB 0/I rate of 68% (123/183) (95% CI: 61%–75%). When assessed by germline BRCA status, pCR rate was 56% (75/133) in BRCA wild-type and 59% (16/27) in BRCA mutation-associated TNBC (P=0.83). Due to the inclusion of a small number of patients with 1–10% ER/PgR expression, pCR assessment was also performed according to ER/PgR expression status. 50% and 55% of patients with ER/PgR 1–10% (N=6) and ER/PgR <1% (N=177), respectively, achieved pCR (P=1.0).

Survival outcomes

At a median follow-up of 36 months (range: 4–97 months), there have been 36 RFS events (distant N=26, local/regional N=5, site of metastasis unknown N=5) and 25 deaths, with estimated 3-year RFS and OS of 79% (95% CI: 73%–85%) and 87% (95% CI: 82%–92%), respectively (supplemental figure 2). Figure 2 shows Kaplan-Meier curves for RFS and OS by pCR (panels A–B) and RCB 0/I (panels C–D) status. Patients achieving pCR demonstrated significantly better RFS and OS compared to patients without pCR. Estimated 3-year RFS was 90% and 66% in patients with and without pCR, respectively (HR=0.30; 95% CI: 0.14–0.62, P=0.0001). Estimated 3-year OS was 94% (95% CI: 89%–99%) and 79% (95% CI: 70%–88%) for patients with and without pCR, respectively (HR=0.25; 95% CI: 0.10–0.63, P=0.001). Similar to those who achieved pCR, patients who achieved RCB 0/I status also demonstrated significantly superior RFS and OS compared to patients with RCB II/III. Estimated 3-year RFS was 91% (95% CI: 86%–96%) and 59% (95% CI: 45%–73%) in patients with RCB 0/I and RCB II/III, respectively (HR=0.20; 95% CI: 0.10–0.41, P<0.0001). Estimated 3-year OS was 95% (95% CI: 91%–99%) and 75% (95% CI: 63%–87%) for patients with RCB 0/I and RCB II/III, respectively (HR=0.16; 95% CI: 0.06–0.42, P<0.0001). Figure 3 shows RFS and OS by the four RCB classes. Estimated 3-year RFS was 90% (95% CI: 84%–96%) for RCB 0 (pCR), 93% (95% CI: 79%–100%) for RCB I, 69% (95% CI: 54%–84%) for RCB II, and 21% (95% CI: 0%–46%) for RCB III. Estimated 3-year OS was 94% (95% CI: 89%–99%) for RCB 0 (pCR), 100% for RCB I, 83% (95% CI: 71%–95%) for RCB II, and 43% (95% CI: 11%–75%) for RCB III. Compared to patients with RCB II, patients with RCB III had inferior RFS (HR=4.70; 95% CI: 1.97–11.20, P<0.0001) and OS (HR=4.34; 95% CI: 1.59–11.84, P=0.002). RFS appeared similar between RCB 0 (pCR) and RCB I groups (HR=2.48; 95% CI: 0.32–19.36, P=0.37). Due to the absence of OS events in the RCB I group, no formal statistical analysis was done to compare OS between RCB 0 and RCB I groups.

Figure 2:

(A) Recurrence-free survival by pCR status; (B) Overall survival by pCR status; (C) Recurrence-free survival by RCB 0/I vs RCB II/III; (D) Overall survival by RCB 0/I vs RCB II/III.

^a RCB unavailable for 3 patients

Figure 3:

(A) Recurrence-free survival by RCB class; (B) Overall survival by RCB class.

^a RCB unavailable for 3 patients

When analyzed by BRCA status, estimated 3-year RFS was 88% (95% CI: 75%–100%) in patients with germline BRCA1/2 mutation and 79% (95% CI: 72%–86%) in patients who were BRCA wild-type (HR=0.69; 95% CI: 0.24–1.99, P=0.48). Similar to RFS, estimated 3-year OS was similar between patients with germline BRCA1/2 mutation (95%, 95% CI: 86%–100%) and those who were BRCA wild-type (87%, 95% CI: 81%–93%) (HR=0.37; 95% CI: 0.12–2.21, P=0.33)

Adjuvant chemotherapy use and survival

Only 5 out of 100 patients with pCR received postsurgical adjuvant chemotherapy (all 5 received doxorubicin and cyclophosphamide, AC). Adjuvant chemotherapy use in patients with pCR did not impact RFS or OS (data not shown). None of the 23 patients with RCB I status received adjuvant chemotherapy. Fifty eight percent (33/57) of patients with RCB II/III received adjuvant anthracyclines, and the survival outcomes in this group were not significantly different compared to those patients who did not receive adjuvant anthracycline (supplemental figure 3). No patients received adjuvant capecitabine.

Factors impacting survival

On univariate analysis, baseline node-positive status, higher baseline T stage, lack of pCR, and an RCB greater than 0/I were all predictors of a greater risk of recurrence and death, whereas age at diagnosis, BRCA mutation status, pathological grade, and adjuvant chemotherapy use (in patients with RCB II/III) did not impact RFS and OS (table 2). On multivariable analysis, higher baseline T stage was associated with greater risk of recurrence and death, whereas RCB 0/I was associated with reduced risk of recurrence and death. Baseline node-positive status was associated with greater risk of recurrence but not of death.

Table 2:

Univariate and multivariate analysis of RFS and OS

UNIVARIATE ANALYSIS
	RFS		OS
Variable	HR (95% CI)	P	HR (95 % CI)	P
Age
< 50	1		1
> 50	0.90 (0.47–1.73)	0.75	0.60 (0.27–1.33)	0.20
Lymph node status
Negative	1		1
Positive	4.47 (1.96–10.21)	<0.0001	5.40 (1.85–15.74)	0.001
T stage
1/2	1		1
3/4	4.56 (2.30–9.02)	<0.0001	6.11 (2.55–14.65)	<0.0001
Histological grade
1/2	1		1
3	1.18 (0.57–2.46)	0.66	0.56 (0.19–1.64)	0.26
Germline BRCA mutation
Negative/unknown	1		1
Positive	0.69 (0.24–2.00)	0.49	0.51 (0.12–2.21)	0.29
pCR
No	1		1
Yes	0.30 CI (0.14–0.61)	0.0005	0.25 (0.10–0.63)	0.001
RCB
II/III	1		1
0/I	0.20 (0.10–0.41)	<0.0001	0.16 (0.06–0.42)	<0.0001
RCB
II/III	1		1
I	0.09 (0.01–0.67)	0.003	0.027 (0.00–2.16)	0.006
Adjuvant chemotherapy (in patients with RCB II/III)
Yes	1		1
No	1.30 (0.56–3.03)	0.54	0.75 (0.27–2.08)	0.58
MULTIVARIATE ANALYSISa
RFS              OS
II/III	1		1
Variable	HR (95% CI)	P	HR (95 % CI)	P
RCB
II/III	1		1
0/I	0.30 (0.14–0.63)	0.002	0.26 (0.10–0.70)	0.008
T stage
1/2	1		1
3/4	2.28 (1.07–4.86)	0.032	2.79 (1.06–7.36)	0.038
Lymph node status
Negative	1		1
Positive	2.51 (1.04–6.03)	0.040	2.47 (0.79–7.74)	0.12

^aVariables included age, lymph node status, T stage, pathological response, RCB class, germline mutation status, adjuvant chemotherapy

Adverse Events

As previously reported (29), 28% (54/190) of patients in the intent-to-treat population experienced one or more grade 3/4 adverse events (Grade 3 = 21%, Grade 4 = 7%) (table 3). Of the per-protocol population, 88% (161/183) of patients completed all 6 cycles of treatment. Twelve percent (22/183) discontinued treatment prematurely: 4.4% (8/183) because of progressive disease, 6.0% (11/183) because of toxicity, 1.6% (3/183) because of other reasons. No treatment-related deaths were reported.

Table 3:

Grade 3 to 4 treatment-related toxicities

N = 190	Grade 3/4      N (%)	Grade 3     N (%)	Grade 4      N (%)
Leukopenia	2 (1%)	2 (1%)	0 (0%)
Neutropenia	22 (12%)	13 (7%)	9 (5%)
Thrombocytopenia	11 (6%)	9 (5%)	2 (1%)
Anemia	7 (4%)	6 (3%)	1 (1%)
Febrile neutropenia	8 (4%)	6 (3%)	2 (1%)
Nausea	5 (3%)	5 (3%)	0 (0%)
Vomiting	5 (3%)	4 (2%)	1 (1%)
Mucositis	2 (1%)	2 (1%)	0 (0%)
Diarrhea	5 (3%)	5 (3%)	0 (0%)
Peripheral neuropathy	3 (2%)	3 (2%)	0 (0%)
Fatigue	2 (1%)	2 (1%)	0 (0%)
Othera	9 (5%)	9 (5%)	0 (0%)

^aOther: Hepatic/transaminase elevation (n=3), rash (n=2), hyponatremia (n=1), thrombosis (n=1), allergic reaction (n=1), dehydration (n=1).

Discussion

In this study, we demonstrate that CbD NAC regimen yields a high pathological response rate (55%), which translates to encouraging 3-year RFS and OS. Recent randomized trials demonstrate that the addition of carboplatin to anthracycline and taxane-based NAC improves pathological response from 37–41% to 50–58% in TNBC (11, 19, 21, 22, 27). The pCR rate of 55% with this CbD regimen appears to be comparable to the pCR rate noted when carboplatin is added to anthracycline-taxane chemotherapy and numerically higher than classical neoadjuvant anthracycline-taxane combinations, where 28–40% of TNBC patients achieved pCR (11, 21, 33). Long-term benefits from the addition of neoadjuvant platinum to anthracycline/taxane regimens in TNBC are not yet clear. The Cancer and Leukemia Group B (CALGB) 40603 randomized phase II trial evaluated the addition of carboplatin and/or bevacizumab to a standard chemotherapy regimen of weekly paclitaxel followed by AC in TNBC and demonstrated improvement in pCR rates with the addition of carboplatin (41% vs 54%; P=0.003). In this trial, however, the addition of carboplatin did not lead to improvement in 3-year event-free survival (71% vs 76%, P=0.36) (11). The GeparSixto randomized phase II trial reported that addition of weekly carboplatin to the combination of paclitaxel, nonpegylated liposomal doxorubicin, and bevacizumab improved pCR rate (37% vs 53%, P=0.005), and unlike CALGB 40603, at a median follow-up of 3 years demonstrated a 44% improvement in 3-year disease-free survival (DFS) (76% vs 85%, P=0.0325) in patients with TNBC (21, 34). It is possible that differences in the chemotherapy backbones of the control arm between CALGB 40603 and GeparSixto (i.e. absence of the alkylating agent cyclophosphamide in the control arm of GeparSixto) could have contributed to the differences in the long-term outcomes noted in the two studies. However, it is noteworthy that neither CALGB 40603 nor GeparSixto were sufficiently powered for DFS and OS endpoints; several ongoing, adequately powered, randomized phase III trials are evaluating the efficacy of adjuvant platinums in the context of AC-plus-taxane chemotherapy in TNBC (NCT02488967, NCT02455141, NCT02441933). In our study, where more than half of patients had node-positive disease and a third had stage III disease, we report 3-year RFS and OS of 79% and 87%, respectively. These findings are in line with 3-year outcomes reported from GeparSixto (48% node-positive) and CALGB 40603 (58% node-positive) and also compare favorably with outcomes noted in contemporary adjuvant trials of AC plus taxane in TNBC (35, 36).

In a recently reported germline BRCA-focused subgroup analysis of GeparSixto, pCR and DFS benefit from the addition of carboplatin was observed primarily in patients without germline BRCA mutation (37). BRCA mutation carriers experienced a high pCR rate of 66.7% with the anthracycline+taxane+bevacizumab regimen, and this rate was not increased further by addition of carboplatin. In contrast, in patients with BRCA wild-type TNBC, the addition of carboplatin increased pCR from 36% to 55%. Regardless of the treatment regimen, DFS was generally high in BRCA mutation carriers, with no significant difference separated by study arms, whereas in patients with BRCA wild-type TNBC, better DFS was noted in the carboplatin arm (HR=0.53; 95% CI: 0.29–0.96; P=0.04).These findings suggest that the substantial homologous recombination deficiency induced by germline BRCA mutation may be therapeutically responsive to most types of DNA-damaging chemotherapy, including anthracyclines, and that this responsiveness is not improved further by addition of a platinum agent. However, the homologous recombination deficiency brought about by mechanisms other than germline BRCA mutation may not be as robust, and could therapeutically respond to targeting by platinum agents, even in the presence of anthracyclines. Further translational research is needed to understand mechanisms of homologous recombination deficiency in BRCA wild-type TNBC and their relationship to platinum response.

Previous studies and meta-analyses have demonstrated that pCR is a robust surrogate for improved long-term outcomes in aggressive breast cancer subtypes like TNBC (3, 38). The positive impact of pCR on long-term outcomes (event/disease-free and overall survival) was also observed in both GeparSixto and CALGB 40603 trials. Hazard ratios for the prognostic impact of pCR on RFS and OS noted with the current CbD regimen overlap with hazard ratios noted in the meta-analysis by Cortazar et al and those from both GeparSixto and CALGB 40603. It is noteworthy that for patients with pCR, where only 5% received adjuvant anthracycline-based chemotherapy, we demonstrate 3-year RFS and OS of 90% and 94%, respectively. These findings suggest that the favorable prognostic impact of pCR in TNBC is probably independent of the chemotherapy regimen leading to pCR, a finding which has also recently been noted by the I-SPY 2 investigators (39). An interesting finding of our trial is the excellent outcome of patients who achieved RCB class I pathological response, which was as good as the outcome of those achieving pCR. A similar finding has recently been reported for TNBC patients treated with neoadjuvant anthracycline and taxane-based NAC (40). If confirmed in additional studies, a composite of pCR plus RCB class I pathological response could be more suitable than pCR alone for identification of TNBC patients destined for excellent prognosis following NAC. Two thirds of patients (68%) in this study demonstrated pCR or RCB I with this CbD regimen, and these patients enjoyed very robust 3-year RFS (≥ 90%) and OS (≥ 93%) without adjuvant anthracycline treatment. These data indicate that adjuvant anthracycline can be avoided for patients achieving pCR or RCB with CbD.

Poor outcomes were noted in patients with RCB II and III, particularly so in patients with RCB III, where the 3-year RFS was only 21%. In our study, a modest proportion (58%) of patients with RCB II or III received adjuvant anthracycline-based chemotherapy; however, adjuvant chemotherapy use did not impact outcomes in these patients. These findings highlight the need for and support the ongoing investigations of novel therapies in TNBC patients who have significant residual disease

Anthracyclines and cyclophosphamide, though very active for treatment of breast cancer, carry established small but serious long-term risks (secondary leukemia/myelodysplastic syndrome, cardiomyopathy) (41, 42). Anthracycline-free platinum-taxane chemotherapy regimen is associated with lower incidence of secondary leukemia/myelodysplastic syndrome and cardiomyopathy compared to anthracyclines-cyclophosphamide-taxane regimen when given concurrent with trastuzumab in HER2-positive breast cancer (43). The efficacy of anthracycline-free neoadjuvant combinations in sporadic and BRCA-associated TNBC has not been adequately explored so far. Taxanes are important components of neo/adjuvant chemotherapy regimens for breast cancer treatment and appear to contribute particularly among patients with TNBC (23, 44). Platinum and taxanes are mechanistically distinct, and preclinical and clinical data demonstrate synergy between platinum compounds and taxanes in several solid tumor types, including metastatic TNBC (24–26, 28). In the metastatic setting, the randomized TNT trial demonstrated superior efficacy of single-agent carboplatin over single-agent docetaxel in the presence of germline BRCA mutation but equal efficacy of either agent in the absence of germline BRCA mutation. Furthermore, the TNT trial noted no cross-resistance between the two drugs, with equal response rates noted for both agents upon cross-over (45). The promising efficacy of the neoadjuvant CbD regimen noted in the current study might also be explained by the notion that the combination of docetaxel and carboplatin offers robust antitumor coverage for both basal and non-basal TNBC (45).The encouraging outcomes noted with this CbD regimen provide further evidence for the clinical efficacy of platinum-taxane combination in TNBC. Together, these data provide clinical and biological rationale for further investigation of anthracycline-free, platinum-taxane chemotherapy for early stage TNBC.

Tolerance of the CbD regimen used in this study was good, with only 6% of patients discontinuing therapy because of toxicity. A similar chemotherapy regimen, the TCH regimen (that combines carboplatin and docetaxel with trastuzumab), is widely used for the neo/adjuvant treatment of HER2-positive breast cancer and is likewise associated with a favorable toxicity profile.

Sixteen percent of the current study population carried a deleterious germline BRCA1/2 mutation, which is consistent with expected prevalence of germline BRCA1/2 mutation in TNBC (14, 15). We noted a pCR rate of 59% in BRCA mutation carriers, which is in line with previously reported pCR rates with single-agent platinum chemotherapy in BRCA1 mutation carriers (46). In our study, deleterious BRCA mutation was not associated with 3-year DFS or OS, a finding which is also consistent with previous reports (47, 48). Furthermore, it is becoming increasingly evident that 40–50% of BRCA wild-type TNBC may harbor homologous recombination deficiency (as identified by genomic mutational and transcriptional signatures), and that the benefit of platinum agents may extend beyond BRCA mutation-associated breast cancers (12, 16, 17, 49, 50). Several homologous recombination deficiency assays are being evaluated in clinical and translational research studies; however, assays with demonstrable clinical utility in selecting BRCA wild-type TNBC patients likely to derive preferential benefit from platinum agents are not yet available.

Our study has limitations. First, the decision to combine the two patient cohorts for the purpose of reporting pCR and survival outcomes was made post hoc and was not pre-planned. However, this report includes almost 200 TNBC patients treated uniformly across three different continents. In this combined analysis, more than half of the patients had node-positive disease, and a third had stage III disease. These patient characteristics are very similar to contemporary neo/adjuvant randomized clinical trials for TNBC (11, 36).

Second, we acknowledge the lack of a control arm, a deficit which can only be addressed in the setting of a randomized trial. In fact, an ongoing randomized phase II study is currently comparing neoadjuvant CbD regimen to an anthracycline-taxane-carboplatin regimen (NCT02413320). While we await data from ongoing trials, this regimen may provide an alternative for patients who desire treatment with a platinum regimen but are not candidates for anthracycline. We also acknowledge the modest follow-up of 3 years; however, given the natural history of TNBC, where the majority of recurrence events occur in the first 3 years, longer follow-up is unlikely to significantly change our results (2, 3).

In conclusion, the combination of carboplatin plus docetaxel yielded significant antitumor activity in stage I–III TNBC, with a favorable toxicity profile.

Statement of Translational Relevance:

Phenotypic and molecular similarities between sporadic and BRCA mutation-associated triple negative breast cancer (TNBC) have prompted the exploration of DNA-damaging agents like platinum compounds in TNBC. We report survival outcomes with neoadjuvant carboplatin plus docetaxel, an anthracycline-free chemotherapy regimen, in TNBC. Robust pathological complete response (pCR) and near-complete response (RCB I) rates were noted with this regimen. Patients who achieved pCR or RCB I had excellent three-year recurrence-free and overall survival without adjuvant anthracyclines, suggesting that the composite of pCR+RCB I may accurately identify patients at low risk of recurrence who can avoid further adjuvant chemotherapy and associated toxicities. This platinum-taxane chemotherapy regimen rendered equally high pCR and survival rates in BRCA-associated as in BRCA-wildtype TNBC. The results of our study support further evaluation of platinum-based chemotherapy in both BRCA-associated and wildtype TNBC as well as the role of extent of pathological response in risk stratification of patients undergoing neoadjuvant chemotherapy.