Grace Choong and Matthew Goetz On the Impact of Adjuvant Endocrine Therapy Omission in ER+ Positive Breast Cancer

For patients with estrogen receptor–positive breast cancer who have residual disease following neoadjuvant chemotherapy, endocrine therapy may continue to play a crucial role in the adjuvant setting, according to Grace Choong, MD; and Matthew Goetz, MD. However, there may be reason to consider de-escalating adjuvant endocrine therapy among patients who achieve a pathologic complete response (pCR).¹

The pair recently presented on a poster at the 2022 San Antonio Breast Cancer Symposium. In an interview with Oncology Nursing News®, they discussed the study findings, and the future implications this research might have on the treatment landscape.

The study found that among patients receiving neoadjuvant chemotherapy for estrogen receptor–positive breast cancer (n = 39,394), those with HER2-positive disease (n = 5960) were less likely to have received adjuvant endocrine therapy compared with HER2-negative patients (n = 28,434; 61.6% vs 88.8%, respectively; P < .001). Moreover, in patients with residual disease following neoadjuvant chemotherapy, omission of adjuvant endocrine therapy was linked to a significantly higher risk of death (P < .001).

Additionally, patients who achieved pCR were much less likely to start adjuvant endocrine therapy than those who had residual disease (P < .001). This was consistent in the HER2-negative analysis (78.0% vs 89.1%) and the HER2-positive analysis (44.2% vs 66.2%).

“I think the most interesting result that we got is that [among patients with] estrogen receptor–positive, HER2-positive breast cancer who had residual disease, there were quite a few [individuals] who chose to omit adjuvant endocrine therapy,” Choong, who is a resident doctor at the Mayo Clinic, told Oncology Nursing News®. "This was a little higher than we otherwise would have expected, and negatively impacted overall survival [OS].”

“Ultimately, patients who have residual disease would benefit from proceeding with adjuvant endocrine therapy, but in those patients who have [achieved] pCR we could potentially consider adjuvant endocrine therapy admission,” she added.

Neoadjuvant chemotherapy is used to downstage tumors and increase breast conservation. However, for patients with estrogen receptor–positive breast cancer, pCR rates following neoadjuvant chemotherapy are low, and tend to vary greatly by HER2 status. Adjuvant endocrine therapy may be implemented to reduce the local and distant recurrence risk, boosting OS, but, as the study authors note in the interview, adjuvant therapy can represent be challenging for patients who have just completed chemotherapy because of the toxicity burden associated with a daily pill.^2-4

“When patients go through their neoadjuvant therapy, there’s a group of patients who are tired, they have gone through sometimes 20 weeks of therapy, and they often think the hard part of their of their treatment is over,” Goetz, a medical oncologist with the Mayo Clinic, noted. “I always tell my patients that the hard part is actually starting now, that is, after you finish your chemotherapy—because you have to take this pill every day.”

Therefore, investigators sought to understand how endocrine therapy adherence rates were intertwined with survival outcomes in this setting, in both patients with and without a pCR.¹

The investigators queried the National Cancer Database for female patients with stage I-III estrogen receptor–positive breast cancer who received neoadjuvant chemotherapy prior to surgery. Patients were stratified by HER2 expression. Time-dependent covariates using Cox proportional hazards ratios were used to analyze OS with adjuvant endocrine therapy.

A total of 4505 patients achieved a pCR, comprising of 9.1% of patients in the HER2-negative and 32.0% of the HER2-positive subgroups. Across the subgroups, patients who achieved pCRs were significantly less likely to initiate adjuvant endocrine therapy than those with residual disease, and among those with residual disease, those with HER2-positive disease were less likely to initiate adjuvant endocrine therapy than those with HER2-negative disease.

Moreover, at a follow-up of 4.4 years, the 5-year OS rates among patients with estrogen receptor–positive, HER2-negative disease who achieved pCR was 94% (95% CI, 92%-95%). The OS among patients with estrogen receptor–positive, HER2-positive positive disease who achieved pCR was 95% (95% CI, 94%-97%). For patients with residual disease, the 5-year OS rates between the 2 groups were 83% (95% CI, 82%-84%) and 88% (95% CI, 86%-89%), respectively.

In a multivariable analysis, patients with residual disease who omitted adjuvant endocrine therapy experienced significantly poorer OS rates in both the HER2-positive (adjusted HR, 1.63; 95% CI, 1.37-1.94; P < .001) and HER2-negative subgroups (adjusted HR, 1.72; 95% CI, 1.58-1.87; P < .001). However, among patients who achieved pCR, omission of adjuvant endocrine was not significantly associated with varying OS outcomes in either the HER2-positive populations (adjusted HR, 1.13; 95% CI, 0.77-1.66; P = .54) or the HER2-negative (adjusted HR; 1.28, 95% CI, 0.88-1.87; P = .20)

According to study authors, this research is “hypothesis gathering” but has strong implications for de-escalating adjuvant therapy in patients who achieve pCR with neoadjuvant chemotherapy.

Although both Choong and Goetz agreed that more research is needed in this space for endocrine therapy omission, the findings reinforce the potential benefit of adjuvant endocrine therapy for patients with residual disease.

“What this research highlights is the importance of continuing to counsel our patients and clinicians so that if [patients] have residual disease, even if they have estrogen receptor–positive, HER2-positive breast cancer,[they know] there is a strong benefit in their favor if they proceed and get adjuvant endocrine therapy,” Choong concluded. “We realize that there's a huge treatment burden for these patients with her HER2-positive disease both in the neoadjuvant and adjuvant settings for HER2-directed therapies, but that additional adjuvant endocrine therapy is something that we should counsel our patients more on and try to increase their adherence rates and hopefully improve their OS.”

References

1. Choong GM, Boughey JC, Hoskin TL, et al. Impact of adjuvant endocrine therapy (ET) Omission in ER+ breast cancer (BC) treated with neoadjuvant chemotherapy (NAC). Presented at 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.
2. von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012;30(15):1796-1804. doi:10.1200/JCO.2011.38.8595
3. Burstein HJ, Lacchetti C, Anderson H, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: ASCO clinical practice guideline focused update. J Clin Oncol. 2019;37(5):423-438. doi:10.1200/JCO.18.01160
4. Yussof I, Mohd Tahir NA, Hatah E, Mohamed Shah N. Factors influencing five-year adherence to adjuvant endocrine therapy in breast cancer patients: A systematic review. Breast. 2022;62:22-35. doi:10.1016/j.breast.2022.01.012