Adaptive Therapy Approach in HER2+ Early Breast Cancer May Improve Outcomes, Expert Says

An adaptive therapy approach for treating HER2-positive early breast cancer in both the adjuvant and neoadjuvant settings may assist in reducing toxicity and improving outcomes for a range of patients with different baseline disease characteristics.

“For node-negative [disease], the outcomes are pretty good, so we would want to use the less toxic weekly paclitaxel and trastuzumab [Herceptin] regimen,” said Debu Tripathy, MD, at the 38th Annual Miami Breast Cancer Conference, hosted by Physicians’ Education Resource®, LLC (PER®),¹ when discussing options for adjuvant therapy. “But for node-positive disease, we are going to want to use the more intensive disease chemotherapy…and dual antibody therapy.”

Other options for patients with node-positive disease include treatment in the neoadjuvant setting, since risk can be further stratified by an in vivo real-time assay. Moreover, at the time of surgery, the achievement of pathological complete response (pCR) can be further used to determine what treatment in the adjuvant setting can be used in these patients.

Personalization of Therapy

In his presentation, Tripathy, who is a professor and chairman of the department Breast Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, explored different adjuvant and neoadjuvant therapy approaches for treating patients with early-stage, HER2-positive breast cancer by chemotherapy and HER2-targeting agents.

“In the last few years, there have been the development of numerous new HER2-targeted therapies,” Tripathy said. The ones that are used for early-stage disease include trastuzumab and pertuzumab (Perjeta), which bind directly to HER2 and can interfere with its function; tyrosine kinase inhibitors, such as lapatinib (Tukysa) and neratinib (Nerlynx), which work on the intracellular portion of the HER2 receptor by inhibiting kinase activity and downregulating signaling; and immunoconjugates like T-DM1 (Kadcyla), which is similar to the structure of trastuzumab, but with highly toxic compounds allowing internalization into the cell and are specifically released into the payload to cause cell death.

Tripathy detailed the basic requirements of personalization, which involve knowing the natural history of the disease, familiarity with therapeutic effects of each therapy as well as toxicities which may affect vulnerable populations, awareness of clinical factors or biomarkers which may predict response, and awareness of the data regarding risk- or biomarker-adapted approaches.

The first way to approach risk-adaptive therapy is to identify patients who already have known low-risk disease, although Tripathy acknowledged it is difficult to perform randomized trials regarding therapy benefit in this group.

“What we know historically from patients who are treated with HER2-targeted therapies for T1a and T1b tumors…the outcomes are very good regardless of [whether or not they received treatment],” Tripathy said.

Adjuvant Therapy Selection

In the adjuvant setting, data from the ATEMPT trial have shown that the use of T-DM1 versus trastuzumab and paclitaxel for early HER2-positive breast cancer induced high rates of disease control with similar rates of adverse events. However, toxicity profiles varied between the 2 regimens, with T-DM1 resulting in more treatment delays.²

“Overall, the toxicity rates were equal, but they were distributed differently,” Tripathy said. “There was more neurotoxicity with the weekly paclitaxel but more early treatment discontinuation due to T-DM1 due to other side effects such a thrombocytopenia, neurotoxicity, and liver function test abnormalities.”

The NeoSphere trial (NCT00545688) demonstrated that patients receiving pertuzumab in addition to trastuzumab and chemotherapy as adjuvant therapy had improved long-term outcomes, although achievement of pCR regardless of therapy was a strong indicator of long-term outcomes in all of the trial’s therapy arms.³

From there, Tripathy directed attention to the KATHERINE trial (NCT01772472), which examined trastuzumab versus T-DM1 for patients with residual invasive disease after neoadjuvant therapy. Results of that trial showed a 50% reduction in disease recurrence or death with T-DM1 (P <.0001).⁴

“This was an improvement in outcome, essentially a doubling, of the number of patients who recurred with trastuzumab only,” Tripathy said.

The ExteNET trial (NCT00878709) of extended adjuvant neratinib following neoadjuvant and adjuvant chemotherapy and trastuzumab showed reduced clinically relevant breast relapses without increasing long-term toxicity.⁵

From these results, Tripathy said patients with node-negative disease can be treated with standard paclitaxel and trastuzumab. For those with node-positive disease, patients can receive trastuzumab/paclitaxel plus pertuzumab and from there, the pCR status will determine if patients receive another round of trastuzumab/pertuzumab (pCR) or T-DM1 followed by neratinib (no pCR).

References:

1. Tripathy D. Personalizing Neoadjuvant and Adjuvant HER2-Targeted Therapy. Presented by: 38th Annual Miami Breast Cancer Conference, hosted by Physicians’ Education Resource®, LLC (PER®); March 4-7, 2021.

2. Tolaney SM, Hu J, Dang C, et al. TBCRC 033: A randomized phase II study of adjuvant trastuzumab emtansine (T-DM1) vs paclitaxel (T) in combination with trastuzumab (H) for stage I HER2-positive breast cancer (BC) (ATEMPT). Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14; San Antonio, TX. Abstract GS1-05

3. Gianni L, Pienkowski T, Im YH, 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. doi: 10.1016/S1470-2045(16)00163-7

4. von Minckwitz G, Huang CS, Mano MS; KATHERINE Investigators. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med. 2019;380(7):617-628. doi: 10.1056/NEJMoa1814017

5. Martin M, Holmes FA, Ejlertsen B, et al; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(12):1688-1700. doi: 10.1016/S1470-2045(17)30717-9