The Conundrum of Estrogen-Receptor Signaling in HER2-Positive Breast Cancer

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Ruth O’Regan, MD

Given the toxicity of everolimus…as well as the availability of multiple other agents…, it seems unlikely that the mTOR inhibitor will be developed further for metastatic HER2-positive breast cancer.

—Ruth O’Regan, MD
The differential effects based on hormone receptor expression warrant further investigation, particularly in the hormone receptor–positive setting….

—Ruth O’Regan, MD

BOLERO-1—reviewed in this issue of The ASCO Post—is the next installment in a series of randomized trials evaluating the addition of everolimus (Afinitor) to standard therapy in metastatic breast cancer.1 The initial evaluation of everolimus in the HER2-positive metastatic setting looked extremely promising, with data suggesting that the mTOR inhibitor could perhaps reverse resistance to trastuzumab (Herceptin).2 Unfortunately, larger randomized trials1,3 have failed to confirm the initial hopes that everolimus would be a significant addition to the evolving armamentarium for HER2-positive metastatic disease. BOLERO-3, which evaluated the addition of everolimus to trastuzumab and vinorelbine in the trastuzumab-resistant setting, showed a modest improvement in progression-free survival of just over 1 month at initial analysis, which was not confirmed by central analysis.3 BOLERO-1, which evaluated the addition of everolimus to trastuzumab and paclitaxel in the first-line setting, showed no improvement for patients in the investigational arm.1 Progression-free survival in the control arms in both BOLERO trials was more or less consistent with similar trials in this setting.4-7

Differences in Benefit

However, the intriguing finding of different outcomes based on hormone-receptor status initially noted in BOLERO-3 was additionally shown in BOLERO-1. In BOLERO-3, subgroup analysis demonstrated an improvement in progression-free survival, with a hazard ratio of 0.65 in patients with HER2-positive, hormone receptor–negative cancers, compared with a hazard ratio of 0.93 in HER2-positive, hormone receptor–positive cancers.3 Progression-free survival stratified by hormone-receptor status was even more striking in BOLERO-1, where patients with HER2-positive, hormone receptor–negative cancers had an increase in progression-free survival from 14 months in the control group to 20 months in the investigational arm, although this did not meet significance per the criteria of the trial. As with BOLERO-3, there was no benefit to the addition of everolimus in patients with HER2-positive, hormone receptor–positive cancers.1 In the other randomized trials4-7 that accrued patients with HER2-positive metastatic breast cancer, such impressive differences based on hormone receptor were not noted.

The key question regarding this difference in benefit from the addition of everolimus based on hormone receptor is whether cancers that are HER2-positive but hormone receptor–negative specifically benefit from the addition of mTOR inhibition to trastuzumab and chemotherapy or whether HER2-positive, hormone receptor–positive cancers fail to benefit, or perhaps even have a worse outcome, when the HER2 pathway is inhibited in the absence of estrogen-receptor blockade.

In support of the former possibility, patients on the investigational arm of BOLERO-1 had a median progression-free survival of 20 months, which is consistent with (though somewhat longer than) the overall progression-free survival in other first-line trials, such as CLEOPATRA.4 Overall, however, it would appear more likely that the combination of HER2 and mTOR inhibition enhances estrogen-receptor signaling, resulting in relative resistance to HER2-directed therapies. Considerable cross-talk exists between the HER2 and estrogen-receptor pathways, and preclinical studies have shown that inhibition of HER2 in breast cancer models that are additionally estrogen receptor–positive results in the induction of estrogen-receptor signaling.8,9

From a clinical standpoint, the addition of estrogen-receptor inhibition to dual HER2 inhibition increased the response rate in patients with HER2-positive, estrogen receptor–positive cancers treated in the preoperative setting.10,11 Therefore, it is possible, as suggested by Hurvitz et al,1 that the addition of hormone-receptor inhibition to mTOR and HER2 inhibition in these BOLERO trials might have improved outcomes for patients with HER2-positive, hormone receptor–positive breast cancers.

Distinct Subtypes, Different Biology

The natural biology of HER2-positive, hormone receptor–positive cancer remains incompletely understood. Emerging data suggest that these cancers are heterogeneous, with at least two distinct subtypes.9 Using intrinsic subtyping,12 a majority of these cancers are either luminal A or luminal B, which would be expected to have very different biologic courses and response to available therapies.

The finding that almost one-third of these HER2-positive, hormone receptor–positive cancers are luminal A,12 known to have a poor response to chemotherapy, may contribute to the universal finding that HER2-positive cancers that are hormone receptor–positive have a lower complete response rate to preoperative chemotherapy than hormone receptor–negative cancers.9 In support of this differential response to preoperative chemotherapy in HER2-positive, hormone receptor–positive cancers, another study showed a low complete response rate to preoperative trastuzumab-based chemotherapy in cancers with high expression of hormone receptors, with a higher response rate in those with moderate to low expression levels.13

However, trials to date that have evaluated the omission of chemotherapy in patients with HER2-positive, hormone receptor–positive breast cancers demonstrate higher response rates with trastuzumab-based chemotherapy compared with dual HER2 and estrogen-receptor inhibition in the absence of chemotherapy—although none of these trials stratified patients based on subtype of HER2-positive, estrogen receptor–positive cancer.11,14

Molecular Analysis of HER2-Positive Cancers

There have been elegant molecular studies performed on tumor specimens from the BOLERO-1 and BOLERO-3 trials in an attempt to identify a biomarker that could justify the further development of everolimus in the HER2-positive setting.15 Lack of PTEN and mutation of PI3 kinase are both associated with a benefit from the addition of everolimus to trastuzumab-based chemotherapy. Patients with tumors lacking PTEN had a 23-month progression-free survival with the addition of everolimus to trastuzumab-based chemotherapy in BOLERO-1.

Some key differences between hormone receptor–negative and hormone receptor–positive breast cancers were identified using next-generation sequencing, with a higher rate of mutations in TP53 and a lower rate of mutations in CCND1, FGFR, and GATA3 noted in hormone receptor–positive cancers.15 This finding supports the existence of key differences between HER2-positive breast cancers according to hormone-receptor status.

Further Development?

Results from these BOLERO trials beg the question of whether everolimus should be further developed in the HER2-positive setting for patients with hormone receptor–negative cancers, as well as perhaps for cancers that lack PTEN. There was significant toxicity noted in BOLERO-1, which resulted in dose reductions, suggesting that the optimal dose of everolimus when given with chemotherapy is 5 mg.1

Given the toxicity of everolimus, although this can be managed proactively, as well as the availability of multiple other agents, either approved or in development, it seems unlikely that the mTOR inhibitor will be developed further for metastatic HER2-positive breast cancer. However, the differential effects based on hormone-receptor expression warrant further investigation, particularly in the hormone receptor–positive setting, where it seems possible that some cancers could be treated with targeted agents alone without the use of chemotherapy. ■

Disclosure: Dr. O’Regan is an advisor to and has received research support from Novartis and Genentech.


1. Hurvitz SA, Andre F, Jiang Z, et al: Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): A phase 3, randomised, double-blind trial. Lancet Oncol 16:816-829, 2015.

2. Andre F, Campone M, O’Regan R, et al: Phase I study of everolimus plus weekly paclitaxel and trastuzumab in patients with metastatic breast cancer pretreated with trastuzumab. J Clin Oncol 28:5110-5115, 2010.

3. Andre F, O’Regan R, Ozguroglu M, et al: Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3). Lancet Oncol 15:580-591, 2014.

4. Baselga J, Cortés J, Kim SB, et al: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109-119, 2012.

5. Gelmon KA, Boyle FM, Kaufman B, et al: Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2-positive advanced breast cancer: Final results of NCIC CTG MA.31. J Clin Oncol 33:1574-1583, 2015.

6. Ellis PA, Barrios CH, Eiermann W, et al: Phase III, randomized study of trastuzumab emtansine ± pertuzumab vs trastuzumab + taxane for first-line treatment of HER2-positive metastatic breast cancer: Primary results from the MARIANNE study. 2015 ASCO Annual Meeting. Abstract 507.

7. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783-1791, 2012.

8. Xia W, Bacus S, Hegde P, et al: A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer. Proc Natl Acad Sci U S A 103:7795-7800, 2006.

9. Paplomata E, Nahta R, O’Regan RM: Systemic therapy for early stage HER2-positive breast cancers: Time for a less-is-more approach? Cancer 121:517-526, 2015.

10. 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. J Clin Oncol 31:1726-1731, 2013.

11. Gianni L, Pienkowski T, Im YH, et al: Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere). Lancet Oncol 13:25-32, 2012.

12. Carey LA, Barry WT, Pitcher B, et al: Gene expression signatures in pre- and post-therapy specimens from CALGB 40601 (Alliance), a neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer. 2014 ASCO Annual Meeting. Abstract 506.

13. Bhargava R, Dabbs DJ, Beriwal S, et al: Semiquantitative hormone receptor level influences response to trastuzumab-containing neoadjuvant chemotherapy in HER2-positive breast cancer. Mod Pathol 24:367-374, 2011.

14. Harbeck N, Gluz O, Christgen M, et al: Efficacy of 12 weeks of neoadjuvant TDM1 with or without endocrine therapy in HER2-positive hormone-receptor-positive early breast cancer: WSG-ADAPT HER2+/HR+ phase II trial. 2015 ASCO Annual Meeting. Abstract 506.

15. Slamon DJ, Hurvitz SA, Chen D, et al: Predictive biomarkers of everolimus efficacy in HER2+ advanced breast cancer: Combined exploratory analysis from BOLERO-1 and BOLERO-3. 2015 ASCO Annual Meeting. Abstract 512.

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