De-Escalation Possible in Curative Setting for HER2+ Breast Cancer

Ciara O'Sullivan, MB, BCh

Treatment de-escalation for patients with HER2-positive breast cancer is feasible and imperative, explained Ciara O’Sullivan, MB, BCh, and as the field continues to evolve, more efforts will be directed at tailoring HER2-directed therapies more effectively.

Studies have assessed and confirmed the benefit of de-escalating therapy for patients with early-stage HER2-positive breast cancer. For example, 7-year follow-up data from the APT trial showed that patients with HER2-positive lesions and negative lymph nodes may not necessarily need additional HER2-targeted therapy. Results from the analysis demonstrated a 93.3% disease-free survival rate with the use of adjuvant paclitaxel and trastuzumab (Herceptin) for 12 weeks, followed by 39 weeks of weekly trastuzumab.¹

The NSABP B-52 trial evaluated the regimen of docetaxel, trastuzumab, and pertuzumab (Perjeta) alone or in combination with endocrine therapy in patients with hormone receptor—positive, HER2-positive breast cancer. These patients went on to have surgery, with a primary endpoint of pathologic complete response (pCR).

Results demonstrated a numeric improvement in pCR for breast and nodes, increasing from 40.9% to 46.1% with the addition of estrogen deprivation. An increase in pCR of the breast was also observed, going from 44.2% to 47.4% with the addition of estrogen deprivation.² Although these findings were numerically significant, they were not determined to be statistically significant. Investigators concluded that the addition of estrogen deprivation to neoadjuvant chemotherapy was not antagonistic nor increased toxicity. Due to the toxicity observed with standard chemotherapy in the trial, the findings supported the need for a de-escalation approach without compromising patient outcomes.

Investigators also must identify accurate and reproducible biomarkers of response and resistance, O’Sullivan added, as the disease is heterogeneous and not every patient will benefit from the same treatment approach.

OncLive: What is the prevalence of HER2-positive breast cancer and what is the general prognosis for these patients?

Could you give an overview of your presentation on the curative setting for HER2-positive disease?

How can HER2-targeted treatment be more individualized?

What are some of the biggest challenges that still exist in this space?

Where is the field headed in the next 5 to 10 years?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Breast Cancer, O’Sullivan, a family physician at Mayo Clinic, discussed the need for treatment de-escalation for patients with HER2-positive breast cancer, as well as the challenges that remain in tailoring treatment.O’Sullivan: HER2 is seen in approximately 15% to 20% of patients and, prior to the advent of adjuvant trastuzumab, patients were noted to have a more aggressive clinical course and poor outcomes. Since the advent of trastuzumab and the newer HER2-directed therapies, there has been a dramatic improvement in treatment in both adjuvant metastatic settings. However, approximately 15% to 25% of patients ultimately relapse. So, the onus is on us to find more effective therapies for those patients.My presentation focused on treatment escalation and de-escalation for patients with HER2-positive breast cancer. In terms of the treatment escalation portion of my presentation, I discussed the role of adjuvant pertuzumab and neratinib (Nerlynx), and their role in the treatment armamentarium. In terms of treatment de-escalation, I discussed the importance of appropriately selecting patients for less toxic treatments, because a lot of those patients will do just as well without polychemotherapy and additional HER2-directed regimens.HER2-positive breast cancer is heterogeneous, and different patients will benefit from different treatment approaches. The identification of accurate and reproducible biomarkers of response and resistance will be important in terms of being able to tailor treatment more effectively going forward. We haven't identified those biomarkers. Ongoing efforts are in progress; potential candidates would include looking at the molecular intrinsic subtypes of HER2-positive breast cancer as well as immune infiltrates. Also, treatment de-escalation is feasible and important and, really, the majority of patients benefit only a slight degree from the addition of newer HER2-targeted treatment regimens in the adjuvant setting.[The biggest challenge is] resistance to HER2-directed therapies. Although we have come a long way in terms of the efficacy of HER2-directed treatment, and patients are now a lot less likely to relapse, for those patients who do relapse, we need to understand more about mechanisms of resistance and develop more effective, novel therapies.The field will continue to evolve, and with progress, additional questions [will present themselves]. There will be many additional efforts in trying to tailor HER2-directed therapies more effectively, in terms of treatment de-escalation and escalation. The results of existing and ongoing trials and studies of existing HER2-directed therapies used in combination with novel therapies, such as immunotherapy and the CDK4/6 inhibitors, will help us inform treatment decision making going forward.

References

1. Tolaney SM, Barry WT, Guo H, et al. Seven-year (yr) followup of adjuvant paclitaxel (T) and trastuzumab (H) (APT trial) for node-negative, HER2-positive breast cancer (BC). J Clin Oncol. 2017;35(suppl 15):511. doi: 10.1200/JCO.2017.35.15_suppl.511.
2. Rimawi MF, Cecchini RS, Rastogi P, et al. A phase III trial evaluating pCR in patients with HR+, HER2-positive breast cancer treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) +/- estrogen deprivation: NRG Oncology/NSABP B-52. In: Proceedings from the 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, Texas. Abstract S3-06. doi: 10.1158/1538-7445.SABCS16-S3-06.