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HER2+ EBC: Evolution

CE / CME

The Evolving Therapeutic Landscape for HER2-Positive Early-Stage Breast Cancer

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: August 10, 2020

Expiration: August 09, 2021

Lee Schwartzberg
Lee Schwartzberg, MD
CME/CE Information

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Why Use Neoadjuvant Systemic Therapy?

Turning now to patients with more extensive or higher-risk HER2-positive EBC, let's start by taking a step back and considering why neoadjuvant systemic therapy has become increasingly more important in the treatment of EBC over the past few years.

The use of adjuvant HER2-targeted therapy with trastuzumab plus a chemotherapy backbone has been a standard of care in breast cancer for approximately 15 years. What has shifted in recent years is the increasing use of neoadjuvant (ie, preoperative) chemotherapy.[18,19] There are several advantages to neoadjuvant therapy in breast cancer treatment.

First and foremost, neoadjuvant therapy can result in tumor shrinkage before surgery and, in many instances, allows patients who have larger tumors to undergo breast conservation surgery as opposed to a total mastectomy. In addition, the use of sentinel lymph node biopsy can decrease the need for axillary surgery and thereby reduce the chance of lifelong lymphedema. Of note, neoadjuvant chemotherapy generally yields the same outcome as standard adjuvant chemotherapy, so the impact on survival is essentially equivalent. But, neoadjuvant therapy also allows both the patient and the physician to observe the tumor’s response to therapy; in some subtypes of breast cancer, any additional adjuvant therapy approaches can be selected based on the response to neoadjuvant therapy.

One of the most important reasons to use systemic neoadjuvant therapy is to assess the likelihood of a pathologic response at surgery. The use of pathologic CR (pCR) as a surrogate biomarker for long-term outcomes in patients with breast cancer is well established, based on multiple trials and meta-analyses. This means the amount of residual cancer that’s left at surgery is highly prognostic and, therefore, can help guide not only additional neoadjuvant recommendations for therapy but also the choice of postsurgical adjuvant systemic therapy.

CTNeoBC Pooled Analysis: Association Between pCR and Event-Free Survival

In 2014, a meta-analysis of clinical trials with neoadjuvant treatment of early breast cancer (the CTNeoBC pooled analysis) supported the concept of pCR as a surrogate marker for long-term outcomes with HER2-targeted therapy in breast cancer.20 In this pooled analysis, 12 international clinical trials that enrolled patients from January 1990 to August 2011 with primary breast cancer treated with preoperative chemotherapy followed by surgery and a median follow-up of ≥ 3 years were included (N = 11,955). In this analysis, patients with HER2-positive EBC who received trastuzumab had a higher rate of pCR compared with those who did not receive trastuzumab. This was true regardless of hormone receptor status, as shown in the bar graph. Furthermore, those who achieved a pCR had improved event-free survival compared with those who did not achieve a pCR.

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Who Should Be Considered for Preoperative Systemic Therapy for HER2-Positive EBC?

Established criteria exist to help determine which patients with HER2-positive EBC should be considered for preoperative systemic therapy.21 The recommendations vary depending on the particular subtype of breast cancer. For the HER2-positive subset, we believe that almost every patient with a tumor greater than 2 cm (ie, T2) or with node-positive disease (ie, stage II) should receive neoadjuvant chemotherapy, regardless of hormone receptor status. In addition to chemotherapy, these patients should receive the HER2 antibodies trastuzumab and pertuzumab, as a part of neoadjuvant systemic therapy.

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

The data that support the use of dual HER2 antibody therapy are from 2 key studies: NeoSphere and TRYPHAENA.

NeoSphere was an open-label, phase II trial of neoadjuvant therapy, including various combinations of chemotherapy, trastuzumab, and pertuzumab, in patients with HER2-positive EBC and no previous chemotherapy (N = 417).22 In this study, patients were randomized to 4 cycles of 1 of 4 regimens: trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m2, escalating, if tolerated, to 100 mg/m2 every 3 weeks) or pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks) and trastuzumab plus docetaxel or pertuzumab and trastuzumab, or pertuzumab plus docetaxel.

Following surgery, all patients received standard adjuvant therapy with 5-fluorouracil/epirubicin/cyclophosphamide as well as continued trastuzumab to complete 1 year of HER2-targeted therapy. The primary endpoint was the pCR rate.

The phase II TRYPHAENA trial (N = 225) was designed as a cardiac safety study, and compared standard neoadjuvant treatment with sequential approaches in patients with HER2-positive EBC.23 Patients were randomized to receive anthracycline-based treatment (FEC) plus trastuzumab and pertuzumab for 3 cycles followed by 3 cycles of docetaxel, trastuzumab, and pertuzumab; FEC for 3 cycles followed by 3 cycles of docetaxel, trastuzumab, and pertuzumab; or docetaxel, carboplatin, trastuzumab, and pertuzumab for 6 cycles. The pCR rate was assessed at surgery, and then patients received trastuzumab to complete 1 year.

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NeoSphere: Neoadjuvant Pertuzumab/Trastuzumab Plus Chemotherapy Increases pCR Rates

In NeoSphere, the addition of pertuzumab to neoadjuvant taxane and trastuzumab increased the pCR rate from 29% to 46% (P = .0141); as a result, this approach became a standard of care. This pCR rate was also higher than either of the 2 other arms: trastuzumab plus pertuzumab without a taxane (pCR: 16.8%) or taxane plus pertuzumab (pCR: 24.0%).

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

In TRYPHAENA, we also saw a similar result, although efficacy was not the primary endpoint and pCR rate was not powered for direct comparison. All treatment arms included the dual HER2-targeted therapy with pertuzumab and trastuzumab and showed high pCR rates. In this analysis, the pCR rate was stratified by hormone receptor status. All 3 regimens resulted in very high pCR rates in hormone receptor–negative patients, with lower pCR rates, although still quite substantial, in those who were hormone receptor positive.

Based on these 2 trials, the FDA granted accelerated approval of the combination of trastuzumab and pertuzumab in combination with chemotherapy as neoadjuvant therapy for HER2-positive EBC. Today, this is standard of care for patients with HER2-positive EBC who require neoadjuvant therapy.

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