ONCAlert | Upfront Therapy for mRCC

Neoadjuvant Chemotherapy Considerations in Triple-Negative Breast Cancer

Nicholas McAndrew, MD, and Angela DeMichele, MD, MSCE
Published Online: Feb 14,2018

Angela Demichele, MD, MSCE


The optimal neoadjuvant chemotherapy (NACT) regimen in triple-negative breast cancer (TNBC) has not been clearly defined. Achieving a pathologic complete response (pCR) provides important prognostic information, and, especially in TNBC, is considered a surrogate endpoint for event-free survival. Thus, many neoadjuvant studies in TNBC focus on this as a primary endpoint, and such information may be used for accelerated US Food and Drug Administration approval. Current controversies in the field include: (1) the role of platinumbased compounds; (2) the optimal chemotherapy backbone; and (3) the benefits of additional therapy after surgery. Conflicting results of 2 major studies adding carboplatin to NACT have highlighted the need to balance potential benefits to disease outcomes against increased toxicity. While the PROGECT study suggests efficacy of a nonanthracycline-containing regimen, this is observational data, and evidence in the form of a clinical trial remains to be seen. Data surrounding optimal taxane use support the use of nab-paclitaxel in place of paclitaxel in limited clinical situations. Although bevacizumab may increase pCR rates, this has not translated into survival benefit. Capecitabine shows promise in patients who have not achieved pCR after NACT. The neoadjuvant setting remains an important model for drug development. This review will focus on the most important and most current neoadjuvant trials in women with TNBC.



Accounting for 13% of breast cancer cases annually,1 triple-negative breast cancer (TNBC) is so designated due to the lack of expression of the estrogen (ER), progesterone (PR), and HER2 receptors. TNBC portends the worst prognosis among the major subtypes of breast cancer, and both the limitations in our understanding of the underlying biology and the lack of targeted therapy are primary challenges in treating this disease,2 with cytotoxic chemotherapy remaining the mainstay of systemic treatment. Although TNBCs carry a higher mortality as compared with luminal-type breast cancers (ER/PR-positive [ER/PR+], HER2-negative), neoadjuvant chemotherapy (NACT) is more likely to result in a pathologic complete response (pCR) in patients with TNBC primary tumors than in those with luminal tumors.3 Pathologic complete response is an important endpoint because patients who attain this status after surgery have improved survival, and this improved prognosis is greatest in the more aggressive subtypes of TNBC and HER2- positive-only tumors.4

In addition to the prognostic information gained from pathologic analysis of the primary tumor after NACT, it also provides researchers an opportunity to expeditiously determine a drug’s efficacy. Studying drugs in the adjuvant setting depends on the timeto- event (ie, recurrence); however, the neoadjuvant setting provides evidence of treatment effects immediately after surgery. Although benefit in the neoadjuvant setting is thought to predict survival in the adjuvant setting, this is not clearly established, and caution should be taken when extrapolating pCR data into true survival endpoints.5 Thus, the neoadjuvant setting remains an important model for drug development. This review will focus on the most important and most current neoadjuvant trials in women with TNBC.

Addition of Carboplatin

Carboplatin is an attractive drug for use in TNBC due to its particular relevance to the pathobiology of TNBC. About 80% of BRCA1 mutation‒associated breast cancers are triple-negative, and are generally regarded as particularly sensitive to interstrand cross-linking agents, such as platinum analogs, due to the defect in homologous recombination (HR)-based DNA repair characteristic of a BRCA1 mutation.6 Additionally, a subset of TNBC tumors exhibit similar defects in HR-based DNA repair, even in the absence of a germline BRCA mutation,7 and these tumors may be carboplatin-sensitive.8 Singleagent, platinum-based therapy has had varied success in metastatic TNBC, with prospective studies reporting response rates that vary from 10% to 40%.9

More recently, 2 studies have investigated the addition of carboplatin to standard-combination NACT in patients with TNBC. The CALGB 40603 study,10 conducted in the United States, was a phase II, 2 × 2 factorial trial that investigated the benefit of adding carboplatin, bevacizumab, or the combination to taxane/anthracycline-based chemotherapy. The trial enrolled 443 women with stage II/III TNBC into 1 of 4 arms. The chemotherapy backbone was 12 weeks of weekly paclitaxel (80 mg/m2), followed by dose-dense doxorubicin and cyclophosphamide (ddAC) every 2 weeks for 4 cycles (60 mg/m2 and 600 mg/m2, respectively), which formed the control group to 3 experimental arms: (1) bevacizumab 10 mg/kg every 2 weeks for 9 cycles; (2) carboplatin area under the curve (AUC) 6 every 3 weeks for 4 cycles; and (3) both bevacizumab and carboplatin, dosed as above. These arms gave the experimental drug(s) concurrently with paclitaxel, with bevacizumab also partially overlapping with the ddAC treatment period.

The addition of carboplatin significantly increased the pCR rate compared with control, from 46% to 60% (OR, 1.76, P = .0018).10 While the addition of bevacizumab resulted in a similar pCR rate, the combination of both agents resulted in the numerically highest pCR rate of 67%. However, in the subsequent survival analysis, adding carboplatin did not significantly impact survival.11 The absolute benefit in 3-year event-free survival (EFS) of adding carboplatin was 4.9% (76.5% vs 71.6%, respectively; HR, 0.84; 95% CI, 0.58-1.22; P = .36). Overall survival (OS) differences were also not significant, with 81.9% OS in the carboplatin group versus 84.6% without carboplatin (HR, 1.15; 95% CI, 0.74-1.79;
P = .53).11 Furthermore, toxicity was higher in the carboplatin group, with those who received carboplatin being less likely to complete therapy without skipping doses, requiring a dose modification, or discontinuing therapy early. Grade ≥3 neutropenia and thrombocytopenia were also more common in the carboplatin group (56% and 20%, respectively) as
compared with control (22% and 4%, respectively).10

These results conflict with those in the Gepar- Sixto trial. In GeparSixto,12 a total of 595 patients with centrally confirmed TNBC were enrolled into 2 groups, with both groups receiving 18 weeks of weekly paclitaxel, weekly nonpegylated liposomal doxorubicin, and bevacizumab every 3 weeks. The experimental arm additionally received weekly carboplatin. A total of 333 women completed treatment in the combined arms. In the TNBC subgroup, carboplatin resulted in a significantly improved pCR rate over control (53% vs 37%; P = .005). This 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]).12

Clearly, the outcomes were better in the Gepar- Sixto trial compared with CALGB 40603. However, there are several differences between these 2 studies worth noting. GeparSixto had more-favorable baseline characteristics, as 26% of patients in GeparSixto were cN0, compared with 42% in CALGB 40603. Additionally, a larger proportion were cT1 in GeparSixto (26% vs 11%). The backbone therapy was also more intensive in GeparSixto, although this would be expected to affect all arms. In CALGB 40603, the backbone therapy also included cyclophosphamide, which can also cause DNA damage like platinum agents, potentially making the treatment effect similar in the control and experimental arms. Last, the dosing intervals were more compact in GeparSixto, which would potentially allow for less time for DNA repair. Toxicity was greater in the carboplatin- containing arms of both studies, but more grade 3/4 toxicities were seen in GeparSixto relative to CALGB 40603. There are also no data on the long-term effects of these experimental regimens because the median follow-up time was only 3 years.

With these 2 studies in mind, the decision to add carboplatin to a NACT regimen remains an individualized one. Although the hazard ratios suggest benefit, its small size suggests that many patients do just fine without the addition of carboplatin, and can be spared the toxicity. When considering the addition of carboplatin, the backbone regimen and dosing schedule of carboplatin may be critical to optimal efficacy of the drug. If carboplatin is added, clinicians should be cautious given the unknown longterm effects of the added toxicity.

A recent study also worth noting combines carboplatin with another drug aimed at exploiting HR-based DNA repair deficiencies. The I-SPY 2 investigators conducted a phase II study of the adaptive randomization of adding veliparib and carboplatin to the paclitaxel portion of weekly paclitaxel followed by doxorubicin and cyclophosphamide, with pCR being the primary endpoint.13 Veliparib, a potent inhibitor of oral poly(ADP-ribose) polymerase (PARP), was chosen because of preclinical trials showing that it potentiates the antineoplastic effects of carboplatin.14 In patients with TNBC, the pCR rate in the experimental arm was 51% versus 26% in the control arm, resulting in a 99% probability of superiority over control, and an 88% probability of success in a phase III clinical trial. The toxicity profile was similar to that in the CALGB 40603 trial. While this combination appears to improve the rate of pCR compared with control, it is impossible to separate the effects of carboplatin and veliparib. Preliminary data from the Brightness Study presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting helps to clarify this issue.

The Brightness Study randomized 634 patients with resectable, early-stage TNBC to neoadjuvantly receive 1 of 3 paclitaxel-AC‒containing arms: veliparib with carboplatin, carboplatin, or backbone therapy alone.15 There was no difference in pCR rate between the 2 carboplatin-containing groups (53.2% with veliparib/carboplatin vs 57.5% with carboplatin; P = .36), and both carboplatin-containing groups had a higher pCR rate than the control group (31%; P <.001 in both groups).15 These data suggest that the benefit seen in the I-SPY 2 trial was primarily due to carboplatin. Survival outcomes for the Brightness Study are still pending.

Additional studies investigating the role of adjuvant platinum-based therapy are currently ongoing. An ECOG-ACRIN study (E1131, NCT02445391)16 randomizes patients who have residual TNBC after NACT to 2 arms: cisplatin or carboplatin versus capecitabine. An NRG study (NRG-BR003, NCT02488967),17 though excluding patients who had received prior NACT, is investigating the addition of carboplatin to AC-paclitaxel solely in the adjuvant setting, and may provide further insight into the efficacy of carboplatin in TNBC.

Necessity of Anthracyclines

Anthracyclines are effective in early-stage breast cancer, but carry long-term cardiovascular and secondary leukemia risks.18,19 The PROGECT study20 sought to determine whether an anthracycline-sparing regimen would be sufficiently efficacious to enable patients to forgo treatment with an anthracycline. The study was a prospective registry of 2 cohorts from Kansas and Spain composed of 190 patients with stage I-III TNBC, who were either BRCA1/2 carriers (16%) or noncarriers. These patients received neoadjuvant CbD, consisting of carboplatin (AUC 6) and docetaxel (75 mg/m2) every 3 weeks for 4 to 6 cycles. After NACT and surgery, residual cancer burden and pCR were evaluated.

The overall pCR rate was 55%, with BRCA status having no significant impact on pCR. The authors note that this is similar to the pCR rate achieved when carboplatin is added to anthracycline-containing regimens.20 Patients with stage III disease had a significantly lower likelihood of achieving pCR (37%), although these patients comprised about 30% of the study population, and about half the patients had node-positive disease. The authors also note that the toxicity profile of CbD was more favorable than anthracycline- containing regimens. Whereas only 50% to 76% of patients complete all cycles of carboplatin/ anthracycline-containing regimens, upwards of 83% of patients taking CbD completed all treatment.

The results of this observational study are promising. Although an initial analysis of the Kansas-only population reported a slightly higher pCR rate,21 a major criticism was that this high rate may reflect selection bias due to higher numbers of patients with node-negative disease. However, in the combined analysis, nodal demographics were similar to those of other randomized, neoadjuvant TNBC clinical trials. With a substantial pCR rate and favorable toxicity profile, the CbD regimen warrants further investigation in a prospective, randomized clinical trial, which is currently ongoing (NCT02413320).

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Neoadjuvant Chemotherapy Considerations in Triple-Negative Breast Cancer
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