Neoadjuvant Therapy Fundamental in TNBC and HER2+ Breast Cancer

Nadia Harbeck, MD, PhD

Neoadjuvant therapy in early breast cancer has evolved during the past 2 decades from use primarily in large inoperable tumors to a standard treatment option for patients with early-stage HER2-positive and triple-negative breast cancer (TNBC). The use of neoadjuvant therapy revolves around achieving a pathological complete response (pCR) to surgery, which have been associated with improved outcomes, according to a review of current research presented at the 15th St. Gallen International Breast Cancer Conference.

“Achieving pathological complete response in surgery is associated with more favorable outcome across all breast cancer subtypes,” commented Nadia Harbeck, MD, PhD, head of the Oncological Therapy and Clinical Trials Unit of the Breast Center of the University of Munich, in Munich, Germany. “Neoadjuvant therapy is a standard for TNBC and HER2+ subtypes of early breast cancer.”

Across studies, pCR has been associated with improved disease-free survival (DFS) in luminal B/HER2- (P = .005), HER2+/nonluminal (P <.001), and TNBC (P <.001) but not in luminal A (P = .39) or luminal B (P = .45) breast cancer. Furthermore, achieving pCR in HER2+ (nonluminal) and TNBC was associated with an excellent prognosis.

“Subtype matters,” Harbeck underscored, showing that the pCR rates varied from 7% in hormone receptor-positive subtypes to 34% in TNBC, she said. Furthermore, pCR was associated with improved event-free survival (EFS) compared with non-pCR in HER2+ breast cancer that is both estrogen receptor negative (ER-) or ER+ (P = .001 all comparisons).

In TNBC, the treatment strategy begins with an offer of BRCA testing and treatment with anthracycline and taxane containing chemotherapy; neoadjuvant platinum may be offered also, Harbeck noted. Chemotherapy, preferably administered neoadjuvantly, is indicated if the tumor is stage T1b N0, according to Harbeck. Achieving pCR strongly correlates with outcome following neoadjuvant chemotherapy in TNBC.

Recent studies have investigated the use of several neoadjuvant schemas to improve pCR. The addition of platinum to standard therapy has been shown to increases pCR independently of BRCA mutation status in TNBC. The phase III GeparSepto trial demonstrated that pCR occurred more frequently in patients treated with nab-paclitaxel (38%) than with solvent-based paclitaxel (29%; P = .00065) across breast cancer subgroups, including TNBC.¹

Promising results have been seen with an anthracycline-free regimen, such as nab-paclitaxel plus carboplatin. The ADAPT HR-/HER2- (TNBC subtrial) demonstrated substantial pCR after 12 weeks of treatment with an anthracycline free regimen. The pCR rate was 28.7% in patients treated with nab-paclitaxel plus gemcitabine versus 45.9% with nab-paclitaxel plus carboplatin (P = .001).²

“Whether this pCR advantage translates into a survival advantage remains controversial and is still under investigation,” she said.

Neoadjuvant therapy in HER2+ breast cancer consists of targeted therapies against the HER2 or HER3 receptors, including trastuzumab, pertuzumab, T-DM1, and lapatinib, according to Harbeck. The HER2+ breast cancer subtype still requires treatment with a standard chemotherapy backbone such as anthracycline plus taxane. In this subtype, chemotherapy, preferably neoadjuvant, is also indicated if the tumor is stage T1b N0.

High risk HER2+ disease showed responses to dual blockade with trastuzumab plus pertuzumab and docetaxel in the NeoSphere trial. In this study, pCR was 11.2% with trastuzumab/pertuzumab, 17.7% with docetaxel/pertuzumab, 21.5% with docetaxel/trastuzumab, and 39.3% with docetaxel/pertuzumab/trastuzumab. The 5-year progression-free survival (PFS) rate was 86% with the pertuzumab, trastuzumab, and docetaxel regimen (95% CI, 77-91) compared with 81% with trastuzumab and docetaxel (HR, 0.69; 95% CI, 0.34-1.40).⁴

“It is evident in this age of molecularly defined breast cancer subtypes that a ‘one size fits all’ mindset is not suitable,” Harbeck remarked.

“Today, neoadjuvant therapy may be considered standard in the treatment of TNBC and HER2 subtypes, but we need to explore further the role of targeted therapies in these subtypes, the use of neoadjuvant therapy for treatment de-escalation to avoid overtreatment of patients with pCR, and effective additional therapy options are needed for patients not demonstrating pCR.”

References

1. Untch M, Jackisch C, Schneeweiss A, et al. Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto—GBG 69): a randomised, phase 3 trial. Lancet Oncol. 2016.17(3):345-356.
2. Gluz O, Nitz U, Liedtke C, et al. Comparison of 12 weeks neoadjuvant nab-paclitaxel combined with carboplatinum vs. gemcitabine in triple-negative breast cancer: WSG-ADAPT TN randomized phase II trial. Presented at San Antonio Breast Cancer Symposium [abstract S6-07]
3. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010. 375(9712):377-384.
4. Gianni L, Pienkowski T, Im Y-H, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016. 17(6):791-800.

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In the NOAH trial, neoadjuvant trastuzumab was shown to improve the pCR rate in patients with HER2+ locally advanced breast cancer to 43% versus 22% without trastuzumab. The 3-year EFS was 71% with trastuzumab versus 56% without.³ The importance of achieving pCR was underscored by data from the TECHNO and numerous other trials showing that pCR versus no pCR is a prognostic factor of DFS and overall survival (OS).