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De-Escalating Therapy for HER2+ EBC
De-Escalating Therapy for HER2-Positive Early Breast Cancer: Where Do We Stand Today?

Released: June 22, 2018

Expiration: June 21, 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. An increasingly urgent question in early breast cancer is how to safely and effectively de-escalate systemic adjuvant and/or neoadjuvant therapy, particularly for patients with an actionable mutation like HER2. Two studies exploring this question were presented at the 2018 ASCO annual meeting: the phase III Persephone trial, asking whether 6 months of adjuvant trastuzumab is as effective as 12 months, and the phase II PerELISA trial, evaluating whether preoperative trastuzumab/pertuzumab with an endocrine-only backbone, without chemotherapy, will be effective for triple-positive (ER, PgR, HER2) stage II-III breast cancer. The answer to both is a qualified “no”—at least not yet.

The Persephone Trial
This was a carefully planned randomized, noninferiority phase III trial comparing 12 months vs 6 months of trastuzumab in 4000 women with HER2-positive early breast cancer. The primary endpoint was disease-free survival (DFS) after 500 events. Noninferiority was defined as “no worse than 3% below” the expected “control” arm of 12 months of trastuzumab and the HR was calculated based on a 4-year DFS of 12 months trastuzumab that was estimated at 80%. The presented data included DFS at 4 years of 89.8% with 12 months of trastuzumab vs 89.4% with 6 months of trastuzumab, with an HR of 1.07 (90% CI: 0.94-1.24) and noninferiority P = .01.

However, noninferiority cannot be determined by the numeric DFS alone; rather the HR and the upper limit of the range of the HR should also be considered. Based on the actual DFS of the control arm (nearly 90%, not the estimated 80%), the initial HR of 1.17 was recalculated to 1.30. With the study HR of 1.07 and range from 0.94-1.24, the upper limit of the range of 1.24 was clearly less than 1.30. Thus, the primary endpoint was met, so the study was declared noninferior.

The 4-year OS endpoints were 94.8% v 93.8%, respectively, with an HR of 1.14 (90% CI: 0.95-1.37) and noninferiority P = .0006. The upper limit of noninferiority HR for OS was 1.61. Cardiac toxicity was lower in the 6-month arm, with 4% of patients stopping trastuzumab vs 8% with 12 months (P < .0001), and the 6-month arm had faster recovery, although all patients recovered.

Since patients could be randomized after up to 10 doses of trastuzumab, a landmark analysis after 6 months of trastuzumab was performed for DFS and OS to minimize bias based on time to randomization. In this landmark analysis, the HRs for both DFS and OS were also within the noninferiority range.

The Persephone Trial: Clinical Implications
In the discussion at ASCO, Dr. Piccart noted a few important details to consider for clinical practice:

  1. As designed, the noninferiority upper limit of “below 3% of the control” means that the shorter trastuzumab duration may have a 2% to 3% reduction in DFS. In oncology circles, 2% to 3% is a meaningful number: The 10-year update of the ATAC trial comparing tamoxifen with anastrozole set a new standard for adjuvant endocrine therapy with a difference in DFS of 2.6%.

  2. Like most of the other trials of shorter duration, including the FinHer, PHARE, Short-HER, and SOLD trials, this trial enrolled patients over 8 years (2007-2015), and the treatment paradigm for patients evolved during the course of the trial: Sequencing of chemotherapy and trastuzumab in this trial changed from 80% sequential in 2008-2009 to 70% concurrent in 2015, with an overall average of 50% concurrent vs sequential. Similarly, the chemotherapy regimens changed from nearly 70% anthracycline alone and 30% anthracycline/taxane in 2008 to 25% anthracycline alone and 56% anthracycline/taxane in 2015. In a planned subgroup analysis, a DFS HR of 1.53 (90% CI: 1.16-2.01) for the concurrent trastuzumab group favored the 12-month regimen, which is the accepted standard. Only 10% of patients received treatment with taxane alone, but the Tolaney regimen of paclitaxel weekly x 12 with concurrent trastuzumab for 1 year has shown nearly 93% DFS at 7 years. In the Persephone trial, ~50% of patients had T1 disease and ~60% were node negative, suggesting that de-escalation of treatment using the Tolaney regimen would have been an option.

  3. A planned subgroup analysis also suggests that 12 months of trastuzumab was favored in higher-risk patients: ER negative, taxane chemotherapy without anthracycline, and neoadjuvant chemotherapy.

Although Dr. Piccart did not recommend the shorter schedule, she noted that there were positive aspects to the study: A) patients who are unable to complete the full year of trastuzumab may still have benefit, B) underresourced populations may benefit from at least 6 months of trastuzumab even if resources do not allow the full 12 months, and C) there is potential for a meta-analysis of this and the PHARE trial to identify a population of patients who might not need the full 1 year of trastuzumab through careful biomarker assessment.

Based on these data and other studies asking the same question, I will not change my current clinical practice. I will continue to recommend 12 months of HER2-targeted therapy for my patients with HER2-positive early breast cancer. However, it is reassuring to note that patients who must discontinue HER2-targeted therapy early, due to adverse events or other reasons, will likely still derive benefit from their more limited course of treatment. As Dr. Piccart mentioned, it may be wise to consider de-escalating the chemotherapy, not the targeted therapy, in this patient population.

The PerELISA Trial
The phase II PerELISA trial evaluates Dr. Piccart’s question of de-escalating chemotherapy. Patients with triple-positive (ER, PgR, HER2) tumors have a lower pathologic CR rate to chemotherapy plus HER2-targeted therapy than patients with ER-negative tumors; yet, paradoxically, patients with triple-positive disease who do not achieve a pathologic CR seem to have a better overall outcome vs patients with ER-negative tumors as shown in the Cortazar CTNeoBC meta-analysis. Thus, the PerELISA trial tested replacement of chemotherapy with endocrine therapy in combination with dual HER2-targeted therapy with trastuzumab and pertuzumab. The PerELISA design was similar to the ALTERNATE Trial, using a decrease in Ki67 after pretreatment with letrozole to select endocrine-responsive patients: 64 patients with triple-positive stage II-IIIA breast cancer received letrozole for 2 weeks followed by a biopsy to determine the effect of letrozole on Ki67. Patients with tumors with ≥ 20% decrease in Ki67 were deemed “molecular responders” (n = 44) and continued letrozole with the addition of trastuzumab and pertuzumab for five 3-weekly cycles, followed by surgery. Those with tumors that did not have a decrease in Ki67 were considered “molecular nonresponders” (n = 17), and letrozole was stopped and weekly paclitaxel with dual HER2-targeted therapy was administered. The primary aim of PerELISA was to evaluate the pathologic CR. (In retrospect, given the data from the CTNeoBC meta-analysis, pathologic CR may not have been the best endpoint, although certainly a definitive one.) Secondary aims included correlative biomarker analyses: stromal tumor-infiltrating lymphocytes, PI3K mutation status, and PAM50 subtype analysis.

Of 44 patients in the “molecular responders” who received letrozole plus trastuzumab plus pertuzumab, the pathologic CR rate was 21% vs 81% in the 17 patients in the “molecular nonresponders” who received paclitaxel plus trastuzumab plus pertuzumab. Of the 3 biomarker analyses, only the PAM50 subtype analysis (successful in 42 of 44 patients) was associated with molecular response and pathologic CR; of 40 patients achieving a molecular response, 11 (28%) were HER2 enriched, and in this subset, the pathologic CR rate was 45% (P = .032).

The PerELISA Trial: Clinical Implications
In her discussion, Dr. Piccart noted that nonchemotherapy-based trials need a biomarker to select a population that can achieve a minimum pathologic CR rate of at least 40%. Although Ki67 has been widely used, reproducibility varies; however, the PAM50 subtype analysis appears to be both reproducible and an effective biomarker to select a highly HER2-driven cancer. ASCO/College of American Pathologists updated their HER2 testing guidelines just before this annual meeting to minimize the numbers of patients whose HER2 status was deemed “equivocal.” However, HER2 status alone was insufficient to select a subset that could avoid chemotherapy, and the PerELISA study suggests that intrinsic subtyping to select for HER2-enriched tumors may be a more effective method to define responsiveness to HER2-targeted therapies and the basis for determination of more selective treatment without chemotherapy. 

Although this trial was thought provoking, replacing chemotherapy-based HER2-targeted therapy with endocrine-based HER2-targeted therapy in triple-positive early breast cancer is not ready for clinical practice. Until an effective biomarker is identified to select this highly endocrine-sensitive subset of patients, chemotherapy-based HER2-targeted therapy remains the most effective treatment to decrease the risk of recurrence

In your current clinical practice, what percentage of your patients with HER2-positive early breast cancer do not complete 1 year of HER2-targeted therapy? What is the most common reason that your patients discontinue trastuzumab before completing a full year HER2-targeted therapy? Answer the polling question to see what others are saying and share your thoughts in the comment box below.

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In your current clinical practice, what percentage of your patients with HER2-positive early breast cancer do not complete 1 year of HER2-targeted therapy?
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