Combinations Offer Potential to Overcome Resistance in HER2+ Breast Cancer

C. Kent Osborne, MD

While HER2-targeted therapy has transformed the treatment of patients with breast cancer with HER2-positive tumors, this success is dampened by acquired and de novo resistance to these therapies. Current strategies for overcoming resistance to HER2-targeted agents in early breast cancer were outlined by C. Kent Osborne, MD, during the 2017 St. Gallen International Breast Cancer Conference.

Osborne, director of the Dan L. Duncan Cancer Center at the Baylor College of Medicine, 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 major factors of 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.

&ldquo;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,&rdquo; 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 less than 3 cm in the APT trial of trastuzumab (Herceptin) and paclitaxel.¹

&ldquo;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,&rdquo; Osborne explained. &ldquo;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 a drug like trastuzumab, which binds to and blocks HER2, might be a mechanism for resistance to that thera- py by leaving other receptors in the family active to compensate.&rdquo;

Osborne referenced neoadjuvant trials of anti-HER2 agents in combination with trastuzumab and compared the pathological complete response (pCR) rates of the combination compared with trastuzumab alone. The NeoSphere2 trial of pertuzumab (Perjeta) demonstrated a pCR rate of 29% with trastuzumab alone that was increased to 46% with dual pertuzumab/trastuzumab inhibition of HER2. In the NeoALTTO3 and NSABP B414 trials, the pCR rates with trastuzumab were 30% and 52% versus 51% and 62% with combined trastuzumab plus lapatinib (Tykerb), respectively. The TRYPHAENA5 trial did not have a sole trastuzumab comparator, but a pCR of 55% to 64% was achieved with trastuzumab/pertuzumab combination therapy.

Osborne noted 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 targeted therapy alone. He cited neoadjuvant clinical trials in patients not receiving chemotherapy, including the TBCRC 0066 and PAMELA7 trials of lapatinib and trastuzumab, that demonstrated pCR in 20% to 35% of patients.

&ldquo;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,&rdquo; Osborne commented.

He cited patient selection as crucial to this strategy, and observed that, to date, there is no prognostic marker, although the CALGB 40601 and PAMELA trials both showed more patients with a HER2-enriched subtype achieved pCR. PI3K activation is implicated in resistance to HER2 therapy, and the TRYPHAENA8 and NeoALTTO9 trials showed greater pCR rates in patients with wild-type versus mutant PIK3CA.

However, the TBCRC 006 trial6 of lapatinib plus trastuzumab with and without letrozole failed to show an association by flu- orescence in situ hybridization criteria between pCR rate and PIK3CA mutation status, PTEN level, and ER expression.

Osborne outlined a validation study of these and other markers in which 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.

&ldquo;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 resis- tance,&rdquo; Osborne commented.

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