Background
Triple negative breast cancer (TNBC) is an operational term used to define tumors that lack expression of estrogen receptor (ER), progesterone receptor (PR) and lack amplification or overexpression of human epidermal growth factor receptor 2 (HER2) [
1,
2]. Approximately 20% of breast cancers are TNBC [
3]. A small proportion of TNBCs, including adenoid cystic, secretory, adenosquamous and carcinoma, have low aggressive potential and follow an indolent course. However, the majority of TNBCs, most of which are invasive ductal carcinomas, are associated with high rates of early distant recurrence and short survival times compared to other breast cancer subtypes [
1,
2,
4‐
9]. Almost all women with metastatic TNBC will die of their disease within 5 years of diagnosis [
1,
3,
10,
11]; however, those who remain disease-free 8 years after initial diagnosis rarely die of breast cancer [
1,
2,
4], unlike other breast cancer subtypes.
A subgroup of TNBCs are inherently chemosensitive and achieve a pathological complete response (pCR) following combination anthracycline/taxane-based neo-adjuvant chemotherapy (NACT) [
2,
12‐
16]. These patients have a higher rate of survival compared to those with residual disease [
2,
17,
18]. The basis for this variation in response to chemotherapy and survival remains unclear. TNBCs show considerable molecular heterogeneity, and no predictive markers have been identified to date [
16,
17,
19‐
21]. Consequently, efforts have focused on modifying the standard chemotherapeutic regimen using new therapeutic agents to improve outcome.
The observation that many TNBCs exhibit dysfunction of DNA damage repair pathways [
22,
23] has led to the inclusion of platinum salts in the treatment regimen with improved rates of pCR reported both in
BRCA mutation carriers and in sporadic tumors in several phase II trials [
12,
13,
24‐
29]. These data are encouraging; however, platinum salts are not yet part of the standard treatment for TNBC and a definite survival benefit remains to be demonstrated [
30,
31]. Despite this, carboplatin was added to the NACT regimen for TNBC in our institution in 2013 based on phase II trial data. The aim in this study was to examine the effect of carboplatin on outcome for patients with TNBC and to identify biomarkers predictive of response to treatment and outcome. Outcome data from a retrospective series of 333 patients diagnosed with TNBC, including patients treated with carboplatin added to anthracycline–taxane NACT, are presented. This cohort represents one of the largest clinical cohorts of TNBC in the literature, reported outside of the clinical trial setting.
Discussion
We show in a retrospective series that patients with TNBC who received carboplatin with anthracycline–taxane-based NACT have significantly higher rate of pCR compared to those who received anthracycline/taxane alone. A pCR breast and a pCR breast/axilla, achieved in 58% and 55% of those treated with carboplatin, respectively, were the only independent predictors of survival, although follow-up time was short. In patients who did not received NACT, only traditional parameters of nodal status and tumor size had prognostic significance.
Several studies have shown the favorable association between pCR and outcome [
40‐
43]; patients with TNBC who attain a pCR have an outcome that is comparable to that for patients with non-TNBC who attain a pCR [
2,
14,
15,
44]. It is generally accepted that a pCR breast/axilla is a stronger predictor of outcome than a pCR breast, which was shown in our series where a pCR breast/axilla was a stronger predictor of BCSS than a pCR breast for analyses of BCSS. However, this difference in benefit was not observed for DFS or MFS on multivariate analysis, where both pCR endpoints improved DFS and MFS comparably. The benefit of a pCR in terms of survival shown in our data has been reported by others [
13,
15,
45,
46]. However, the prognostic value of pCR has not yet been validated at trial level, as reported in the pooled analysis of almost 12,000 patients [
15]; and it is likely that other variables affect the relationship between pCR and survival that should be examined in future trials examining the prognostic value of pCR [
46,
47].
The rate of pCR in our series is comparable to that reported in two prospective randomized phase II clinical trials evaluating carboplatin with anthracycline–taxane NACT in stage II-III TNBC. In the GeparSixto trial, carboplatin and bevacizumab resulted in an increase from 37 to 53%, in the rate of pCR in 158 patients [
13]. The Alliance study [
12] reported a pCR of 54% in those treated with carboplatin with an alkylating agent. Similarly, in a smaller series, Ando et al. [
26] reported a pCR in 61% for those treated with carboplatin with anthracycline–taxane. Only the earlier GEICAM randomized trial failed to show any improvement in pCR rate with carboplatin [
48]. The phase II adaptively randomized I-SPY 2 study [
25] which assessed the addition of a poly-ADP-ribose-polymerase (PARP) inhibitor, veliparib, plus carboplatin to anthracycline–taxane NACT also reported a pCR in 51% of those who received veliparib and carboplatin.
The data from these studies are promising; however, the optimal way of incorporating platinum agents in the NACT regimen is not yet established [
49]. In the GeparSixto and Ca.Pa.Be studies, different anthracycline–taxane combinations were used and bevacizumab was given [
13,
28]. The dose of carboplatin also differed between studies: GEICAM [
48], CALGB 40603 [
12] and I-SPY2 [
25] used carboplatin every 3 weeks at an AUC = 6; Ando et al. [
26] used carboplatin every 3 weeks at an AUC = 5; Ca.Pa.Be [
28] used weekly carboplatin at AUC = 2 and the GeparSixto (13) used weekly carboplatin at an AUC = 1.5. In our institution, paclitaxel is given weekly for 12 weeks with carboplatin administered at an AUC = 5 every 3 weeks, followed by dose dense doxorubicin plus cyclophosphamide. Platinum agents are reportedly associated with increased toxicity relative to the standard chemotherapeutic regimen [
12,
13]. Some suggest that carboplatin plus paclitaxel may have less hematological toxicities than carboplatin plus docetaxel [
50‐
52] but others report good tolerance of carboplatin plus docetaxel in an anthracycline-free regimen [
53]. In our cohort, toxicities and treatment delays were increased in those who received carboplatin, nonetheless most of those who received carboplatin but did not complete their still achieved a pCR.
Tumor grade was the only other independent predictor of pCR in this study and is in keeping with reported increased chemo-sensitivity for grade 3 compared to low-grade TNBCs [
16]. This emphasizes the importance of accurate tumor grading in pre-NACT tumor material. Although most TNBCs are grade 3, we and others have recorded that between 16 and 21% of TNBCs are not high grade in series that exclude the low-grade indolent subtypes of TNBC [
54,
55, present series]. Tumour histological type was not a prognostic factor in our series. The proportion of ILC in our series (5%) was greater than the 1% reported by others in 20,000 to 90,000 TNBCs [
54‐
56]. However, it was comparable to the 7.7% of ILC recorded in a series 841 TNBCs [
57], which suggests that the discrepancy may relate to the size of series. Metaplastic carcinomas were also uncommon, but we noted that two-thirds of patients with this subtype were disease-free after a median follow-up of 40 months (range 2–154 months). None of the other parameters examined in this study had prognostic or predictive significance.
Basal status by IHC was not informative, which contrasts with reports of adverse outcome for basal TNBCs [
4] and with data showing higher rates of pCR for ‘Basal-like 1’ TNBCs defined by the TNBC type-4 [
16,
58]. There is, as yet, no consensus on either the definition or on the clinical significance of the basal phenotype. Tumors identified as basal using different platforms overlap [
4,
6,
16,
17,
19,
20,
59], but different platforms do not characterize the same tumors as basal. The majority of TNBCs in our series arose in the sporadic setting; however, a pCR breast was significantly associated with a family history of breast cancer, which may point to enhanced chemo-sensitivity or possibly ‘BRCA-ness’ in those with a family history [
22,
23].
The overall outcome and pattern of recurrence for all patients in our series is in line with that reported by others [
1,
2,
4‐
8]. Early distant metastases were more common that local recurrences as a first event, and the median survival time from first was only 8 months. In the non-neoadjuvant setting, tumor size and nodal status were the only predictors of outcome with a significant positive trend of association between these variables and outcome observed. However, there was no survival difference between patients with pT2 versus pT1 disease or between those with pN1 versus pN0 disease. This is at variance with other reports [
5], in which outcome was related to nodal positivity versus node negative disease and not the number of positive nodes. This inconsistency may be explained by the small number of cases with N1 disease (
n = 48) in our series. A nonlinear correlation between both nodal status and tumor size with outcome in TNBC has been observed by others [
1,
60,
61] which suggests that tumor size and extent may be less valid for TNBC with its more aggressive biological behavior than for breast cancer as a whole.
There were limitations with this study. First, the median follow-up time for the NACT group was 30 months and only 18 months for those received carboplatin, reflecting the change in chemotherapy practice over time. Notwithstanding, the natural history of early recurrences peaking between within 3 years of diagnosis for TNBCs [
1,
2,
4‐
8] mitigates to some degree the effect of short follow-up time on DFS. Also, the size of our series was not large enough to explore prognostic differences between subsets of TNBC. However, this study represents one of the largest clinical TNBC cohorts reported; we identified very few studies, performed outside of clinical trials, with larger cohorts of TNBC patients [
5,
62‐
64]. These focused on surgical procedures [
62,
63] or loco-regional recurrences as primary outcomes [
64‐
66]. Even when clinical trials are included, this cohort represents a large, significant patient sample as only the BEATRICE (
n = 2591) [
65], GeparQuinto (
n = 663) [
66], NSABP-B40 (
n = 479) [
67] and CALGB 40603 (
n = 433) [
12] trials had larger TNBC patient cohorts.
The ypT stage assigned by the reporting breast pathologist at the time of diagnosis was used for analyses. Other systems that measure the degree of response to chemotherapy [
68,
69] were reported inconsistently before 2013 and were not used for analysis. The Residual Cancer Burden score may be more promising than the TNM system for post-NACT staging; it provides an index that is predictive of long-term survival with reports of good reproducibility [
37,
69‐
71]. Finally, 27 patients with low ER expression (1–9% positivity) were included. The optimal treatment for these ‘ER-poor’ cancers is not defined. In our institution, these are treated as ER negative disease, although some receive adjuvant endocrine therapy. Whether including these patients could skew our results is a legitimate question; however, molecular subtype analysis suggests that the majority of these cancers have the same profiles and clinical outcome as ER negative disease [
72,
73].
In summary, our data demonstrate that carboplatin added to anthracycline–taxane NACT significantly improves the rate of pCR in TNBC and that pCR is the only independent predictor of outcome, albeit at relatively short follow-up time. Grade 3 histology was the only other independent predictor of pCR, underscoring the importance of accurate evaluation of grade in TNBCs pre-NACT. Platinum therapy is not yet standard-of-care for TNBC. While awaiting results from phase III trials examining the survival advantage for platinums (NCT02488967; NCT02445391), our results add to the data supporting the incorporation of carboplatin with anthracycline–taxane NACT [
74]. It remains unclear whether all or a subset of TNBCs derive benefit from platinum and identification of predictive biomarkers of response are required.