Predictive, Prognostic Models May Tailor Neoadjuvant Approach in HER2+ Breast Cancer

With the advent of effective drug regimens to treat HER2-positive breast cancer, the use of tailored efforts with neoadjuvant therapy in this space may continue to improve efficacy moving forward, according to Lisa A. Carey MD, ScM, FASCO.¹

“[In the future], better predictive and prognostic models are going to allow us to tailor [response-guided therapies] better, both during the neoadjuvant phase, [and] I would argue as well as during the adjuvant phase,” said Carey, L. Richardson and Marilyn Jacobs Preyer Distinguished Professor for Breast Cancer Research, deputy director for Clinical Science, co-leader of the Breast Program, and co-chair of the Breast Committee of the Alliance National Cooperative Group, UNC Lineberger Comprehensive Cancer Center, in Chapel Hill, North Carolina, during a presentation at the 40th Annual Miami Breast Cancer Conference^®.

Need for Tailored Therapy

With many advances and augmented effectiveness of treatment regimens in the early, non-metastatic HER2-postive space—from the approval of trastuzumab (Herceptin) in 2005, to the addition of dual therapies with pertuzumab (Perjeta), extended adjuvant therapy with neratinib (Nerlynx), and the use of trastuzumab emtansine (T-DM1; Kadcyla) in residual disease—tailored risk has been implemented at an increasing rate, Carey said.

“That gives us the opportunity to tailor our approach…and it also leverages the benefits of neoadjuvant therapy to allow us to guide treatment,” she added.

However, with such increasing survival benefits comes the use of multiple drugs. “The medical regimens are complex; they're also toxic; they're expensive; and they take a long time because we're using a lot of medications, both in the chemotherapy realm as well as in the anti-HER2 realm,” Carey explained. “They're very effective. But we all want to feel a little more rational.”

Therefore, advances in response-guided therapy are key for the HER2-positive breast cancer space, Carey explained.

Ongoing Tailored Efforts

Carey highlighted 2 areas of focus in improving tailored efforts for guided therapy in HER2-positive breast cancer: reducing interventions in anatomic low-risk (T1N0) disease and response-guided treatment.

In the phase 2 Adjuvant Paclitaxel and Trastuzumab (APT) trial (NCT00542451), patients with low anatomic risk received 80 mg/m2 paclitaxel with trastuzumab for 12 weeks, followed by trastuzumab for an additional 9 months.2 APT led to 3-, 5-, and 7-year disease-free survival (DFS) rates of 98.5% (95% CI, 97%-100%), 96.3% (95% CI, 94%-98%), and 93.3% (95% CI, 90%-96%), respectively.

“We know that in T1N0 [disease], we can in fact have tailored therapy and do more rational, less aggressive treatments,” Carey said. “But beyond that, [we] need to leverage the neoadjuvant paradigm, and that allows us to do 2 things. We have high response rates to the drugs that we give. We also see high pathologic complete response [pCR] rates that allow us to tailor both breast-conserving efforts and omission of axillary surgery.”

The phase 3 CALGB 40601 (Alliance) trial (NCT00770809) determined that high response and pCR rates with the addition of anti-HER2 therapy to neoadjuvant chemotherapy improved breast conservation and facilitated the omission of axillary lymph node dissection.³

Surgical results from the CALGB 40601 trial supported the use of neoadjuvant therapy, as 43% of patients who were ineligible for breast-conserving therapy up front (n = 171/292) were then made eligible after receiving neoadjuvant therapy, inducing an 80% success rate.⁴ Further, when evaluating axillary clearance by neoadjuvant therapy, of those with HER2-positive disease with known upfront node positivity, 66% were cleared by neoadjuvant therapy, reducing the need for axillary disection.⁵

To demonstrate the prognostic implications of responses to neoadjuvant therapy, Carey noted that treatment with trastuzumab and neoadjuvant chemotherapy alone in these patients demonstrated lower RFS rates among those with pCR (89% [95% CI, 84%-95%]) and those with residual disease (76% [95% CI, 69%-83%]; HR, 0.42; 95% CI, 0.23-0.78; P = .006).³

“So that allows you to stratify and decide who you want to actually try to do additional interventions in,” Carey explained.

Lastly, in the open-label, phase 3 KATHERINE trial (NCT01772472), investigators evaluated adjuvant T-DM1 or trastuzumab in patients with HER2-positive early breast cancer who were found to have residual invasive disease after receiving neoadjuvant chemotherapy plus anti-HER2–targeted therapy.⁶ At 41 months, the 3-year invasive disease-free survival rates were 88.3% in the T-DM1 arm and 77.0% in the trastuzumab arm (unstratified HR, 0.50; 95% CI, 0.39-0.64; P < .001). Further, the 3-year freedom from distant recurrence rates were 89.7% and 83.0%, respectively (unstratified HR, 0.60; 95% CI, 0.45-0.79).

“This is why we switched to T-DM1 when we have residual disease,” Carey added.

Continued efforts are being made to tailor response-guided therapy in HER2-positive breast cancer, including the COMPASS trials (NCT04266249; NCT04457596) and phase 2 PHERGAIN trial (NCT03161353), while investigators also evaluate the role of biomarkers associated with pCR and RFS.

“To conclude, I'd say HER2-positive breast cancer is largely response driven, outside of T1N0 [disease],” Carey said. “Everything we do after that is basically taking advantage of the response to neoadjuvant therapy. [With] future directions, we're going to get better at this.”

References

1. Carey LA. Response-Guided Therapy in HER2-Positive Breast Cancer. Presented at: 40th Annual Miami Breast Cancer Conference®; March 2-5, 2023; Miami, Florida.
2. Tolaney SM, Guo H, Pernas S, et al. Seven-Year Follow-Up Analysis of Adjuvant Paclitaxel and Trastuzumab Trial for Node-Negative, Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer. J Clin Oncol. 2019;37(22):1868-1875. doi:10.1200/JCO.19.00066
3. Fernandez-MartinezA, KropIE, HillmanDW, et al. Survival, Pathologic Response, and Genomics in CALGB 40601 (Alliance), a Neoadjuvant Phase III Trial of Paclitaxel-Trastuzumab With or Without Lapatinib in HER2-Positive Breast Cancer. J Clin Oncol. 2020;38(35):4s184-4193. doi:10.1200/JCO.20.01276
4. Golshan M, Cirrincione CT, Sikov WM, et al. Impact of neoadjuvant therapy on eligibility for and frequency of breast conservation in stage II-III HER2-positive breast cancer: surgical results of CALGB 40601 (Alliance). Cancer Res Treat. 2016;160(2):297-304. doi:10.1007/s10549-016-4006-6
5. Weiss A, Golshan M, Ollila DW. ASO Author Reflections: Accurately Predicting Nodal pCR Holds the Key to Axillary Surgery De-escalation Strategies. Ann Surg Oncol. 2021;28:5972–5973
6. von MinckwitzG, HuangCS, ManoMS, et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. New Eng J Med. 2019;380:617-628. doi:10.1056/NEJMoa1814017