Dual Targeting Advances in HER2+/HR+ Breast Cancer

The discovery of crosstalk between the HER2 and hormone receptor pathways has led to the promising treatment strategy of dual targeting regimens.

William J. Gradishar MD

The discovery of crosstalk between the HER2 and hormone receptor (HR) pathways led to the promising treatment strategy of dual targeting regimens, explained William J. Gradishar MD, in a presentation at the 2018 Miami Breast Cancer Conference® (MBCC).

“When we target pathways simultaneously, we can enhance the antitumor effect and delay the development of resistance to endocrine therapy,” said Gradishar, interim chief of hematology and oncology at Northwestern University’s Feinberg School of Medicine.


At the MBCC, Gradishar discussed key trials showing the efficacy of dual targeted therapy in HER2+/HR+ breast cancer, and the potential addition of a CDK4/6 inhibitor to further enhance this strategy.The phase III ALTERNATIVE trial randomized 355 women with HER2+/HR+ breast cancer to lapatinib (Tykerb) plus trastuzumab (Herceptin) and an aromatase inhibitor (AI; n = 120), trastuzumab plus an AI (n = 117), or lapatinib plus an AI (n = 118).1

Patients were excluded from enrollment if they were appropriate for chemotherapy per investigator judgment. Prior treatment with endocrine therapy in the neoadjuvant, adjuvant, and/or first-line metastatic settings was allowed, as well as trastuzumab plus chemotherapy in similar settings.

The median PFS was 11 months for women assigned to lapatinib/trastuzumab plus an AI compared with 5.7 months for patients assigned to trastuzumab plus an AI (HR, 0.62; P = .0064). The median PFS was 8.3 months for the lapatinib/AI arm.

Overall response rate (ORR) was 31.7% for the triplet group compared with 18.6% in the lapatinib/AI group and 13.7% in the trastuzumab/AI group. There was a numerical trend in overall survival favoring the triplet that was not statistically significant.


“For those patients where you’re trying to avoid chemotherapy, you can enhance the PFS and improve the response rate with dual HER2 targeting and an endocrine agent,” said Gradishar.The phase II PERTAIN trial enrolled 258 postmenopausal women with HER2-positive, HR-positive locally advanced or metastatic breast cancer. Patients were randomized to receive pertuzumab with trastuzumab (n= 129) or trastuzumab alone (n = 129) in combination with an AI. Based on investigator's discretion, induction chemotherapy could be given for 18 to 24 weeks prior to starting endocrine therapy.2

The median PFS was 18.89 months with the pertuzumab triplet compared with 15.80 months for trastuzumab and an AI alone (HR, 0.65; P = .0070). In patients with measurable disease, the ORR with the pertuzumab combination was 63.3% compared with 55.7% for trastuzumab and an AI alone.

The complete response (CR) rate with the pertuzumab triplet was 7.3%, and 56% of patients had a partial response (PR). In the trastuzumab/AI arm, the CR rate was 0.9% and the PR rate was 54.7%. At the analysis, 26.6% and 27.4% of patients had stable disease (SD), with and without pertuzumab, respectively. The disease control rate (CR + PR + SD) was 89.9% with pertuzumab compared with 83% without.

The median duration of response was 27.10 months with the pertuzumab triplet compared with 15.11 months for trastuzumab and an AI alone. This represented a near doubling in the duration of response between the two arms (HR, 0.57; P = .0181).

Adding a CDK4/6 Inhibitor

“As was true in the ALTERNATIVE trial, dual targeting enhances PFS and increases the response rate,” said GradisharA study recently published in The Lancet Oncology, suggests that the next step in this area might be “not only dual targeting, but also trying to enhance the impact of endocrine therapy by adding a CDK4/6 inhibitor,” said Gradishar.

The phase II NA-PHER2 study accrued 36 patients with previously untreated, histologically confirmed, unilateral, invasive, ER-positive/HER2-positive cancer. Thirty patients were included in this first endpoint analysis.

The study showed that the neoadjuvant combination of palbociclib (Ibrance), pertuzumab, fulvestrant (Faslodex), and trastuzumab cut expression of Ki67 and had a high clinical response.3 Twenty-nine (97%) of 30 patients had a response, including 15 CRs and 14 PRs. At baseline, geometric mean Ki67 expression was 31.9 compared with 4.3 at week 2 and 12.1 at time of surgery.


  1. Gradishar WJ, Hegg R, Im S, et al. Phase III study of lapatinib (L) plus trastuzumab (T) and aromatase inhibitor (AI) vs T+AI vs L+AI in postmenopausal women (PMW) with HER2+, HR+ metastatic breast cancer (MBC): ALTERNATIVE. J Clin Oncol 35, 2017
  2. Arpino G, Ferrero J-M, de la Haba-Rodriguez J, et al. Primary analysis of PERTAIN: A randomized, two-arm, open-label, multicenter phase II trial assessing the efficacy and safety of pertuzumab given in combination with trastuzumab plus an aromatase inhibitor in first-line patients with HER2-positive and hormone receptor-positive metastatic or locally advanced breast cancer. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10; San Antonio, TX. Abstract S3-04.
  3. Gianni L, Bisagni G, Colleoni M, et al. Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer (NA-PHER2): an exploratory, open-label, phase 2 study [published online January 8, 2018]. Lancet Oncol. 2018; 2:249-256. doi: 10.1016/S1470-2045(18)30001-9.