New Tactics Needed for Adjuvant Therapy to Advance in Early HER2-Positive Breast Cancer

Ruth M. O'Regan, MD

Recent research has shown that adding targeted agents to trastuzumab-based chemotherapy regimens in the adjuvant setting may not significantly improve outcomes in patients with early-stage HER2-positive breast cancer. Additionally, data on crosstalk in breast cancer pathways have led clinicians to investigate estrogen receptor (ER) blockade along with HER2 inhibitors for tumors that are both ER- and HER2-positive.

Those were among the insights into adjuvant therapies for HER2-positive breast cancer that Ruth M. O'Regan, MD, offered during a presentation at the 13th Annual International Congress on the Future of Breast Cancer that Physicians’ Education Resource hosted in Huntington Beach, California, in July. O’Regan is a professor in the Department of Hematology and Medical Oncology at Emory University and chief of Hematology and Medical Oncology at the Georgia Cancer Center for Excellence at Grady Memorial Hospital in Atlanta.

Trastuzumab, a HER2 receptor blocker, is well established in the treatment of HER2-positive breast cancer. O'Sullivan et al presented a meta-analysis of patients with HER2-positive breast cancer, including 4220 patients with small (≤2 cm) tumors, at the 2014 American Society of Clinical Oncology Annual Meeting.¹ The patients with small tumors who received trastuzumab had lower rates of recurrence or death after 8 years, regardless of hormone receptor status, tumor size, or nodal status. These findings emphasized the general effectiveness of trastuzumab for small HER2-positive tumors, according to O'Regan.

However, recent trial data do not indicate that additional targeted therapies further improve long-term outcomes of trastuzumab-based regimens. The phase III ALTTO trial² showed the addition of lapatinib, another HER2 receptor blocker, to an adjuvant trastuzumab-based chemotherapy regimen in patients with early-stage HER2-positive breast cancer did not improve disease-free or overall survival after a median follow-up of 4.5 years.

However, O'Regan pointed out that the high rates of disease-free (86%-88%) and overall (94%-95%) survival across the treatment groups emphasizes the effectiveness of trastuzumab and that "It is hard to improve on such good outcomes" when incorporating new strategies.

"We really are making great strides in the treatment of HER2-positive disease [with trastuzumab]," said O'Regan.

Likewise, the BETH trial³ showed that adding bevacizumab, an angiogenesis inhibitor, to trastuzumab-based chemotherapy did not improve invasive disease-free survival or overall survival, which were both extremely high (92% and 96%-97%, respectively), after 38 months.

The phase III APHINITY trial⁴ will test whether the combined trastuzumab, pertuzumab, and chemotherapy regimen, which was recently approved by the FDA for neoadjuvant therapy, will improve invasive disease-free survival in approximately 4800 patients who have undergone surgery for HER2-positive breast cancer. O'Regan stated the results of the APHINITY trial, which are expected in 2016, will be critical for understanding the role of adjuvant therapies in trastuzumab-based chemotherapy.

Scaling Back Therapy

Analyses of clinical trial data in adjuvant early-stage settings have prompted researchers to question whether some patients could benefit from less treatment. “There isn’t a clear indication that using the newer agents we have has necessarily improved outcomes for patients with early-stage HER2-positive breast cancer in the adjuvant setting,” said O’Regan. “Therefore, the question is, are we doing too much? Maybe could we do less for some of these patients.”

Although trastuzumab is highly effective for HER2-positive tumors, recent genomic analysis showed patients with immune-enriched tumors had a higher rate of relapse-free survival compared with patients with immune-nonenriched tumors. Such analysis indicates that determining a tumor's immune signature may help predict which patients respond to trastuzumab, according to O'Regan.

The heterogeneity of HER2-positive cancer phenotypes also introduces the need for new treatment strategies targeting the ER, according to O'Regan. According to a recent study⁵ presented by Carey et al, at the 2014 ASCO Annual Meeting, the majority (~82%) of HER2-positive, hormone receptor-positive cancers had a luminal A or B phenotype, indicating that the tumors had a high ER expression.

Because inhibiting HER2 increases ER-regulated gene transcription, using dual HER2 blockade agents without inhibiting ER may increase ER signaling, allowing the ER to act as an "escape mechanism" for tumor growth, said O’Regan. She said this might explain the lower pathologic complete response (pCR) seen with HER2-positive ER-positive tumors in response to this treatment.

According to O'Regan, simultaneous HER2—ER blockade should be considered. She described a recent study that showed preoperative administration of trastuzumab and lapatinib plus letrozole, an ER inhibitor, for 12 weeks led to a pCR rate of 21% in the HER2-positive, ER-positive tumors.⁶ The NeoSphere trial, which used dual HER2 inhibition without ER inhibition in neoadjuvant chemotherapy, showed a much lower pCR (6%) in patients with HER2-positive ER-positive tumors.⁶

Although O'Regan indicated that simultaneous HER2—ER blockade might allow patients to avoid chemotherapy, she added that, "We need to work out which cancers these are that we can avoid chemotherapy in."

References

1. O'Sullivan CC, Bradbury I, De Azambuja E, et al. Efficacy of adjuvant trastuzumab (T) compared with no T for patients (pts) with HER2-positive breast cancer and tumors ≤2cm: a meta-analysis of the randomized trastuzumab trials. J Clin Oncol. 2014;32:5s(suppl; abstr 508).
2. Piccart-Gebhart MJ, Holmes AP, Baselga J, et al. First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T→L), or their combination (T+L) in the adjuvant treatment of HER2-positive early breast cancer (EBC). J Clin Oncol. 2014;32:5s(suppl; abstr LBA4).
3. Slamon DJ, Swain SM, Buyse M, et al. Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy and trastuzumab ±±bevacizumab in patients with HER2-positive, node-positive or high risk node-negative breast cancer. Presented at: 2013 San Antonio Breast Cancer Symposium; December 10-14, 2013; San Antonio, TX. Abstract S1-03.
4. NIH Clinical Trials Registry. www.clinicaltrials.gov website. Identifier: NCT01358877.
5. Carey LA, Barry WT, Pitcher B, et al. Gene expression signatures in pre- and post-therapy (Rx) specimens from CALGB 40601 (Alliance), a neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer (BrCa). J Clin Oncol. 2014;32:5s(suppl; abstr 506).
6. Rimawi MF, Mayer IA, Forero A, et al. Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006 [published online April 8, 2013]. J Clin Oncol. 2013;31(14):1726-1731.