Combinations Show Promise in Overcoming Resistance to HER2-Targeting Therapy

C. Kent Osborne, MD

Blocking the HER2 pathway has been a highly effective treatment of breast cancer that may be limited by both de novo and acquired resistance.

C. Kent Osborne, MD, Director of the Dan L. Duncan Cancer Center of Baylor College of Medicine in Houston outlined current strategies for overcoming resistance to HER2-targeting agents in early breast cancer today at the 15th St. Gallen International Breast Cancer Conference.

Osborne cited the likely determinants of the initial response to endocrine therapy as HER2 oncogene addiction, deregulation of the PI3K pathway and the tumor microenvironment, including lymphocyte infiltration.

“Acquired resistance is much more complex and is driven by clonal selection or adaptive mechanisms,” he commented.

According to Osborne, “escape routes” involving increased expression or signaling in growth factor receptor pathways are a major factor in resistance. He emphasized the importance of eliminating these escape routes, especially the EGFR/HER2 pathway, by using combined therapies that simultaneously target both the estrogen receptor (ER) and growth factor receptor signaling, thereby blocking the crosstalk between these pathways.

“Oncogene addiction implies that a single genomic abnormality in a tumor drives tumor growth and, consequently, that complete inhibition of this pathway therapeutically should then provide an effective treatment for the patient,” he said using HER2 amplification/overexpression as an example. Osborne pointed out that a 3-year disease-free survival (DFS) rate of 98.7% (P <.0001) was achieved in women with HER2-positive node negative cancer and tumors <3 cm in the APT trial of trastuzumab (Herceptin) and paclitaxel.¹

“Therapies targeting HER2 such as trastuzumab are very effective; however, complete blockade of the HER receptor layer by dual blockade is an improvement, especially in the absence of chemotherapy,” Osborne explained. “The HER2 receptor is a member of a family of 4 receptors, all of which can activate the same downstream pathways, so incomplete blockade of the receptor family by an a drug like trastuzumab, which binds to and blocks HER2, might be a mechanism for resistance to that therapy by leaving other receptors in the family active to compensate.”

Osborne referenced neoadjuvant trials of anti-HER2 agents in combination with trastuzumab and compared the pathological complete response (pCR) rates of the combination compared to trastuzumab alone. The NeoSphere² trial of pertuzumab (Perjeta) demonstrated pCR rate of 29% with trastuzumab alone that was increased to 46% with dual pertuzumab/trastuzumab inhibition of HER2. In the NeoALTTO³, CALGB 40601⁴, and NSABP B41⁵ trials, the pCR rate with trastuzumab was 30%, 40%, and 52%, versus 51%, 51%, and 62% with combined trastuzumab plus lapatinib, respectively. The TRYPHAENA⁶ trial did not have a sole trastuzumab comparator, but a pCR of 55% to 64% was achieved with trastuzumab/pertuzumab combination therapy.

Standard chemotherapy was also administered in these trials; however, combined targeted therapies may allow some patients to forego chemotherapy and be treated solely with combined targeted therapies.

Osborne pointed out that the relatively high pCR rates seen in neoadjuvant trials with drug combinations indicate that there is a subset of patients who may be treated with only targeted therapy. He cited several neoadjuvant clinical trials in patients not receiving chemotherapy, including the TBCR006⁷, and PAMELA⁸ trials of lapatinib and trastuzumab which demonstrated pCR in 20% to 35% of patients.

“Many of these patients had large primary tumors. These data suggest that a significant fraction of patients with HER2 amplified tumors, if they can be identified before treatment, might not need chemotherapy at all, only therapy targeting this potent oncogene,” Osborne commented.

He cited patient selection as crucial to this strategy, and observed that, to date, there is no prognostic marker, although both the CALGB 40601 and PAMELA trials showed more patients with HER2 enriched subtype achieved pCR. PI3K activation is implicated in resistance to HER2 therapy, and the TRYPHAENA⁹, GEPARQUATRO¹⁰, and NeoALTTO¹¹ trials showed greater pCR rates in patients with wild type versus mutant PIK3CA.

However, the TBCRC 066 trial¹² of lapatinib plus trastuzumab with and without letrozole failed to show an association by FISH criteria between pCR rate and PIK3CA mutation status, PTEN level, and ER expression.

Osborne outlined a validation study of these and other markers where his group plans to evaluate samples from the TBCRC 006 and 023 studies and the SOLTI Group by RNA sequence, copy number, targeted DNA mutations, and intrinsic subtypes, including HER2 and PTEN by immunohistochemistry.

“If validated, these markers could be used to select patients for a definitive de-escalation trial of HER2 targeted therapy alone in the future. Resistant patients would be candidates for trials of downstream inhibitors or other strategies to overcome resistance,” Osborne commented.

No funding was reported for this symposium. Osborne is on the advisory boards for Genentech and Astra Zeneca.

References

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2. Gianni L, Pienkowski T, Im YH, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016;17(6):791-800. doi: 10.1016/S1470-2045(16)00163-7.
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8. Prat AA, Cortes CJ, Pare L, et al. PAM50 intrinsic subtype as a predictor of pathological complete response following neoadjuvant dual HER2 blockade without chemotherapy in HER2-positive breast cancer: first results of the PAMELA clinical trial. Abstract presented at: 2016 San Antonio Breast Cancer Symposium; December 8, 2016; San Antonio, TX. Abstract S3-03.
9. Schneeweiss A, Chia S, Hegg R, et al. Evaluating the predictive value of biomarkers for efficacy outcomes in response to pertuzumab- and trastuzumab-based therapy: an exploratory analysis of the TRYPHAENA study. Breast Cancer Res. 2014;16(4):R73. doi: 10.1186/bcr3690.
10. Loibl S, von Minckqitz G, Schneeweiss A, et al. PIK3CA mutations are associated with lower rates of pathologic complete response to anti-human epidermal growth factor receptor 2 (her2) therapy in primary HER2-overexpressing breast cancer. J Clin Oncol. 2014;32(29):3212-3220. doi: 10.1200/JCO.2014.55.7876.
11. Majewski IJ, Nuciforo P, Mittemperher L, et al. PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer. J Clin Oncol. 2015;33(12):1334-1339. doi: 10.1200/JCO.2014.55.2158.
12. 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. 2013;31(14):1726-1731. doi: 10.1200/JCO.2012.44.8027.
13. Osborne CK, Duncan DL, Rimawi M, et al. Overcoming resistance to HER2 targeting agents. Presentation presented at: 15th St. Gallen International Breast Cancer Conference; March 15-18, 2017; Vienna, Austria.

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