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Therapy for High-Risk HER2+ EBC

CE / CME

Planning Therapy for High-Risk HER2-Positive Early-Stage Breast Cancer: Expert Viewpoint

Pharmacists: 1.00 contact hour (0.1 CEUs)

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Nurses: 1.00 Nursing contact hour

Released: May 12, 2021

Expiration: May 11, 2022

Lee Schwartzberg
Lee Schwartzberg, MD
CME/CE Information

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Defining High-Risk, HER2+ EBC

A patient with high-risk HER2+ EBC has ≥10% risk of recurrence after receiving initial therapy with adjuvant treatment, with or without neoadjuvant therapy, and definitive surgery. High-risk patients can be divided into 2 groups: The first group has residual disease after receiving appropriate neoadjuvant chemotherapy and anti-HER2 therapy, and the second group of patients consists of those who received surgery first and have either node-positive disease or have T3 or T4 disease that was resected with any nodal status, including N0.

For lower-risk patients with HER2+ EBC who have T1 disease and are node negative, the standard treatment would be systemic adjuvant therapy, typically with paclitaxel and trastuzumab based on the large, nonrandomized phase II APT trial data.1 The focus of this commentary, however, is on patients with high-risk HER2+ EBC.

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Risk Factors for Recurrence of HER2+ EBC Treated With Trastuzumab-Based Therapy

This prospective, noninterventional study of patients treated with trastuzumab-based therapies in Germany between 2006 and 2012 helps highlight some of the risk factors associated with recurrence of HER2+ EBC.2 The size of the primary tumor is important, and in a multivariable analysis, patients with larger tumors (pT2-4) had a higher risk of recurrence compared with those with smaller tumors (pT1/cis) (HR: 1.92; 95% CI: 1.55-2.39; P <.0001). Patients with node-positive disease had a higher risk of recurrence compared with patients with node-negative disease (HR: 2.11; 95% CI: 1.71-2.61; P <.0001). Patients with hormone receptor–positive breast cancer did better than those with hormone receptor–negative breast cancer (HR: 0.5; 95% CI: 0.46-0.67; P <.0001). Of interest, other factors, like Eastern Cooperative Oncology Group performance status, body mass index, and age, did not make a difference in this study regarding risk of recurrence.

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Introduction to Neoadjuvant Therapy

Neoadjuvant therapy has become an important component of treating many patients with HER2+ EBC, and that is based on an overwhelming body of evidence showing that patients who achieve a pathologic complete response (pCR) do significantly better than patients who have residual disease after appropriate therapy. A patient who has achieved a pCR has no invasive cancer in the breast or in the LNs at surgery, based on current definitions. Residual ductal carcinoma in situ is consistent with the definition of a pCR.

Meta-analysis of the Relationship Between pCR and EFS in Patients With HER2+ EBC

A recently published meta-analysis looked at the relationship between pCR and event-free survival (EFS) and overall survival (OS) in a large patient population.3 Out of 5711 patients with HER2+ breast cancer who received neoadjuvant chemotherapy and anti-HER2 therapy, approximately 90% of those with pCR were still without an event at 9 years. In comparison, for patients with residual disease, more than one half had experienced an event by 9 years. The 95% CIs here are completely nonoverlapping and the HR (0.31) shows almost a 70% better outcome for EFS in patients who achieved a pCR. This translates into an OS advantage as well. For the 1654 patients with HER2+ breast cancer evaluated, there was a greater than 80% improvement in OS for the patients who achieved a pCR.

Based on these and other data, pCR remains a very important marker of outcome for patients with EBC, and this and other studies suggest that how a patient responds to neoadjuvant therapeutic strategies can continue to inform postsurgery outcomes for patients with HER2+ breast cancer.

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Criteria for Neoadjuvant Therapy: HER2+ EBC

The move to treat patients with neoadjuvant therapy has accelerated over time. The current standard is that patients with a tumor ≥2 cm in diameter or patients with node-positive disease—regardless of the size of the primary tumor and hormone receptor status—should receive neoadjuvant systemic therapy with the anti-HER2 antibodies trastuzumab and pertuzumab.4,5

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Pivotal Studies on Neoadjuvant Trastuzumab/Pertuzumab for Patients With HER2+ EBC

Current recommendations are, in part, based on 2 early studies in the neoadjuvant setting. Although small in size, these pivotal trials showed the advantage of adding pertuzumab to trastuzumab and chemotherapy for patients with HER2+ EBC.

The NeoSphere trial was an open-label phase II trial that looked at 4 different treatment strategies in 417 chemotherapy-naive women with HER2+ EBC.6 Patients received various combinations of trastuzumab, pertuzumab, and chemotherapy (docetaxel) in different cohorts before surgery, and chemotherapy (5-fluorouracil/epirubicin/cyclophosphamide) was given after the surgery with trastuzumab to complete what was the standard of care at that time. Patients all received trastuzumab for a total of 1 year. The primary endpoint for the NeoSphere study was pCR in the intention-to-treat (ITT) population.

The TRYPHAENA study was a phase II neoadjuvant study comparing cardiac safety with either an anthracycline-containing regimen or a nonanthracycline-containing regimen plus trastuzumab and pertuzumab.7 In this study, 225 patients with operable, locally advanced or inflammatory HER2+ EBC were evaluated. Unlike NeoSphere, in TRYPHAENA all the patients received chemotherapy prior to surgery, and the pCR rate was assessed at surgery After surgery, patients received adjuvant therapy to complete 1 year of trastuzumab therapy. The primary endpoint for the TRYPHAENA study was cardiac safety.

In both of these studies, patients were eligible if they had tumors ≥2 cm in diameter, but patients with locally advanced cancers were also eligible, including those with inflammatory breast cancer. So, some of the patients had tumors that were larger and borderline operable breast cancers in these trials. 

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NeoSphere: Neoadjuvant Trastuzumab/Pertuzumab + CT Increases pCR Rates

The NeoSphere trial looked at 4 different strategies for achieving a pCR, and the best strategy was docetaxel with pertuzumab and trastuzumab, with 46% of patients achieving a pCR.6 This was substantially better than the previous standard of trastuzumab and taxane alone (29% pCR) and was also better than pertuzumab and taxane (24% pCR).

An interesting group that may be worthy of further exploration was a de-escalation strategy of nonchemotherapy, where 17% of patients achieved a pCR with treatment of trastuzumab/pertuzumab. This is not standard of care today, but clinical trials are exploring various strategies of not using chemotherapy to achieve a pCR in some subsets of patients with HER2+ breast cancer.

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TRYPHAENA: pCR (ypT0/is) by ER/PgR Status

In the TRYPHAENA study, patients received combination chemotherapy upfront prior to surgery, so these results are more representative of what one might expect from the standard way we treat patients today.7 A very high pCR rate was achieved regardless of whether an anthracycline-containing or nonanthracycline-containing regimen was used with the combination of trastuzumab/pertuzumab.

The TRYPHAENA study also showed a difference in pCR outcome based on the hormone receptor status, a finding that has been replicated in other subsequent studies. Patients with ER-negative and PgR-negative status with HER2 positivity had a much higher rate of pCR, whereas only approximately one half of the patients who were hormone receptor positive achieved a pCR regardless of the therapy. In the cohort of 75 patients who received 5-fluorouracil/epirubicin/cyclophosphamide followed by 3 cycles of docetaxel with trastuzumab/pertuzumab, 65.0% of patients who had hormone receptor–negative disease achieved a pCR compared with 48.6% for patients with hormone receptor–positive disease. For patients treated with docetaxel/carboplatin plus trastuzumab/pertuzumab for 6 cycles (n = 77), 84% and 50% of patients with hormone receptor–positive or hormone receptor–negative disease, respectively, achieved a pCR. A similar trend was seen for patients treated with 3 cycles of 5-fluorouracil/epirubicin/cyclophosphamide and trastuzumab/pertuzumab followed by 3 cycles of docetaxel with trastuzumab/pertuzumab. In this case, 79% of patients (n = 73) with hormone receptor–negative disease achieved a pCR and 46% of patients with hormone receptor–positive disease achieved a pCR.

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