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Identifying High-Risk Disease
In HER2-Positive Early Breast Cancer, Who Benefits From Dual HER2-Targeted Therapy? Identifying High-Risk Disease

Released: October 17, 2018

Expiration: October 16, 2019

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The current standard of care for patients with HER2-positive early breast cancer includes chemotherapy plus a total of 1 year of HER2-based therapy in addition to surgery and radiation as needed.  But which patients will benefit the most—or the least—from adjuvant HER2-targeted therapy? In this commentary, I will explore a subset analysis of the very large APHINITY trial that was designed to answer this question.

APHINITY: Main Findings
The phase III APHINITY trial was a very large (N = 4804), randomized, placebo-controlled trial of 1 year of adjuvant pertuzumab added to standard adjuvant chemotherapy plus trastuzumab in patients with HER2-positive early breast cancer. The massive sample size was due to the fact that 37.5% of patients enrolled had lymph node (LN)–negative disease and were expected to contribute very little to the relapse event rate (in fact, the sample size was increased by 1000 and the number of LN-negative subjects was capped during enrollment). In the intent-to-treat population, invasive disease-free survival (iDFS) was significantly improved by the addition of pertuzumab to adjuvant chemotherapy plus trastuzumab, with estimated 3-year iDFS rates of 94.1% vs 93.2% for pertuzumab vs placebo (HR: 0.81; 95% CI: 0.66-1.00; P = .045). However, although this result met statistical significance, the 0.9% absolute difference between the treatment and control arms is arguably clinically irrelevant (and certainly not cost effective by any benchmark). Accordingly, it became necessary to explore data from clinicopathologic subsets of patients within this large trial to determine whether (or not) there are particular subsets of interest who may derive a more clinically meaningful benefit from the incorporation of pertuzumab into the adjuvant setting.

LN-Negative Disease
In preplanned subset analysis, the number of invasive-disease events was low among patients with LN-negative disease (just 32 patients 3.6% in the pertuzumab group and 29 patients 3.2% in the placebo group), with no detectable treatment effect (HR: 1.13; 95% CI: 0.68-1.86; P = .64). Therefore, there is no enthusiasm for treatment of LN-negative HER2-positive disease with adjuvant pertuzumab. Indeed, it has been firmly established that treatment of small LN-negative HER2-positive breast tumors is best accomplished (along with local control measures) by systemic adjuvant therapy with weekly low-dose paclitaxel (80 mg/m2) for 12 weeks in combination with standard adjuvant trastuzumab for 1 year. With this approach, 7-year breast cancer–specific survival is very good: 98.6% (95% CI: 97% to 100%).

The ongoing phase III KATHERINE clinical trial is investigating the hypothesis that the regimen of paclitaxel plus trastuzumab could one day be replaced by the antibody–drug conjugate ado-trastuzumab emtansine (T-DM1). If this approach is successful, it could eliminate the need for chemotherapy altogether in patients with low-risk HER2-positive early breast cancer. However, we still do not know the best way to manage larger HER2-positive cancers that are LN negative. However, inasmuch as HER2 gene amplification is a strong risk factor for presence of nodal metastasis in the first place, so HER2-positive LN-negative cancers are distinctly uncommon (and could even call into question the basis for determination of “HER2-positive” status).  

In the subset of patients in APHINITY with LN-positive disease, the 3-year iDFS rate was 92.0% in the pertuzumab group and 90.2% in the placebo arm (HR: 0.77; 95% CI: 0.62-0.96; P = .02), indicating a greater proportional reduction in risk of iDFS events. Of note, there was no significant difference in the HRs for patients with 1-3 positive LNs vs ≥ 4 positive LNs.

Additional Subset Analysis
Despite some apparent separation between the iDFS curves based on hormone receptor expression, this was not a statistically significant predictor for response to adjuvant pertuzumab: HRs were 0.86 (95% CI: 0.66-1.13) and 0.76 (95% CI: 0.56-1.04) for hormone receptor positive and negative subsets, respectively (P for interaction = .54). Had error bars been included in the hormone receptor subgroups, the difference between the curves would no doubt appear even less impressive. Younger (premenopausal) age was not a predictor for response to adjuvant pertuzumab (HR: 0.99; 95% CI: 0.75-1.32). Indeed, paradoxically, postmenopausal patients fared better with adjuvant pertuzumab (HR: 0.68; 95% CI: 0.51-0.91), with a marginally significant P value for interaction of .07, based on menopausal status. Finally, the P value for interaction based on tumor size (< 2 cm vs 2-5 cm vs ≥ 5 cm) was not significant (P = .20). Indeed, the point estimate on HR was actually lowest in patients with tumors < 2 cm, with HR of 0.62, compared with larger tumors with a HR of 0.96 for tumors 2 cm to < 5 cm and 0.85 for tumors > 5 cm (P for interaction = .20).

In summary, none of the P values for interaction for patient subsets rose to the level of statistical significance, including nodal status, adjuvant chemotherapy type (anthracycline vs nonanthracycline), hormone receptor status, protocol amendment version, age, menopausal status, and tumor size. Therefore, it was not possible for regulators to parse specific subsets for the label indication, which states that pertuzumab is a HER2/neu receptor antagonist indicated for “adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence.” The term “high risk” is otherwise not defined on the pertuzumab label.

Where Does This Leave Clinicians Faced With The Decision of Whether or Not To Use Adjuvant Pertuzumab?
Breast cancer treatment is an “art of medicine” as much as it is science, giving clinicians considerable latitude to use their own judgement in clinical decision making regarding the appropriate use of adjuvant pertuzumab. Certainly, there is no enthusiasm for treating LN-negative patients (rare node-negative large HER2-positive tumors being a possible exception). By contrast, patients with locally advanced (stage III) disease are at sufficiently high risk to merit consideration of adjuvant pertuzumab, even though this subgroup was not well represented in the patient population in the APHINITY trial and, thus, not examined in the subset analysis with statistical rigor. Locally advanced HER2-positive breast cancer is also a high-risk group where extended adjuvant HER2-targeted therapy with neratinib is an option (particularly in estrogen receptor–positive patients where the efficacy signal for neratinib was greater), even though no data support its use in patients who had received adjuvant trastuzumab and pertuzumab.

Patients who fail to achieve a pathologic CR following neoadjuvant HER2-targeted therapy (along with chemotherapy) are also clearly at increased risk for recurrence. Of interest, this group is the target population for the ongoing post-neoadjuvant KATHERINE trial, which is randomizing HER2-positive patients who did not achieve a pathologic CR to complete 1 year of standard adjuvant trastuzumab or T-DM1. If positive, the results from this ongoing trial could be practice changing (depending on magnitude of clinical benefit).

Moving Forward: Identifying Subsets for Adjuvant Therapy With Trastuzumab Plus Pertuzumab
Finally, the lack of concrete evidence to define risk more precisely based on clinicopathologic and demographic subsets in the APHINITY trial begs—in fact, screams—for discovery biomarker research with archived clinical specimens from the trial. Such research is necessary to define high-risk patient subsets using molecular and genetic criteria.

It is already clear based on hierarchical clustering of gene expression data that there are defined subsets within HER2-positive breast cancer with different clinical outcomes. A commercially available 70-gene signature can be used as an independent prognostic indicator to identify patients with HER2-positive early breast cancer who have a favorable long-term outcome. Also, ERBB2 overexpression has been associated with chromoanasynthesis with chromosome 8 (harboring the neuregulin gene locus) and the HER2 locus on chromosome 17, some involving NRG1 fusions with associated ERBB3 overexpression, or even NRG1 gene coamplification along with HER2. Genomic characterization might be able to define a subset of patients with chromosomal structural alterations that act as oncogenic driver events and that could, in theory, respond uniquely to perturbation of ligand-dependent HER2/HER3 heterodimeric mitogenic signaling by pertuzumab.

The pressure is now on for the APHINITY investigators to conduct a robust biomarker discovery campaign to discover predictive markers for pertuzumab response with greater granularity than currently available clinicopathologic and demographic characteristics.

In your current clinical practice, which patients with HER2-positive early breast cancer have you chosen to treat with dual HER2 therapy, including both trastuzumab and pertuzumab? Do these data change your decision making? Answer the polling question to see what others are saying and share your thoughts in the comment box below.

Also, use our Interactive Decision Support Tool to compare your choice of neoadjuvant and adjuvant therapy for your patients with HER2-positive early breast cancer with expert recommendations from me and my colleagues, Frankie Ann Holmes, MD, FACP; Sara Hurvitz, MD, FACP; Joyce O’Shaughnessy, MD; and Denise A. Yardley, MD.
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In your current clinical practice, which patients with HER2-positive early breast cancer do you recommend for adjuvant treatment with dual HER2-targeted therapy including trastuzumab and pertuzumab?
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