Expanding Treatment Options for Hormone Receptor-Positive, HER2-Positive Metastatic Breast Cancer

Read the related article "First-Line Trastuzumab Plus an Aromatase Inhibitor, With or Without Pertuzumab, in Human Epidermal Growth Factor Receptor 2–Positive and Hormone Receptor–Positive Metastatic or Locally Advanced Breast Cancer (PERTAIN): A Randomized, Open-Label Phase II Trial" by Rimawi et al on JCO.org.   Transcript: This JCO Podcast provides observations and commentary on the JCO article 'First-Line Trastuzumab Plus an Aromatase Inhibitor, With or Without Pertuzumab, in HER2-Positive and Hormone Receptor-Positive Metastatic or Locally Advanced Breast Cancer (PERTAIN): A Randomized, Open-Label Phase II Trial' by Rimawi et al.  My name is Sara Tolaney and I am Assistant Professor of Medicine at Harvard Medical School and Senior Physician at Dana-Farber Cancer Institute in Boston, Massachusetts.  My oncologic specialty is breast cancer. Since the seminal report of the benefits of adding trastuzumab to chemotherapy, we have seen an improvement in survival for patients with metastatic HER2-positive disease from approximately two years to now almost 5 years.  This dramatic improvement in outcomes can be attributed to the use of continued anti-HER2 therapy beyond progression as well as the introduction of new HER2-directed therapies.  The largest improvement in survival has come from the addition of pertuzumab to a taxane and trastuzumab as seen within the CLEOPATRA study.  This resulted in an impressive almost 16-month improvement in overall survival and established this regimen as a first line standard in the metastatic setting. While chemotherapy and dual anti-HER2 therapy is the current first line treatment approach, we are now left with the question about how best to optimize therapies available to us, and whether or not there are other first line approaches we could consider in order to lessen toxicity.  One potential alternative approach for patients with hormone-receptor positive, HER2-positive disease could be to consider the use of hormonal therapy.  There has been some concern that hormone-receptor positive tumors that are also HER2-positive may be relatively resistant to hormonal therapy.  One reason for this may be that activation of HER2 can result in direct phosphorylation and activation of the estrogen receptor.  This potential HER2 and ER bidirectional cross-talk has provided justification for combinatorial therapy targeting both of these pathways concurrently.  There have been at least three trials that have examined the addition of single agent HER2-targeted therapy to hormonal therapy.  The TAnDEM trial randomized a little over 200 patients with hormone-receptor positive, HER2-positive breast cancer to either anastrozole alone or in combination with trastuzumab as first line therapy and found a 2.4-month improvement in progression free survival, but no difference in overall survival.  The dual EGFR/HER2 tyrosine kinase inhibitor, lapatinib, has also been investigated in combination with hormonal therapy.  A phase 3 study in the first line metastatic setting found that adding lapatinib to letrozole improved progression free survival from 3.0 to 8.2 months, and another trial that looked at adding lapatinib to fulvestrant found an improvement in progression free survival from 3.3 to 5.9 months.  These three studies suggest that single agent HER2-targeted therapy adds modestly to endocrine therapy, and there has therefore been interest to see if dual HER2 targeted therapy added to hormonal therapy would result in a more significant improvement in outcomes. Since data from CLEOPATRA had suggested that the addition of pertuzumab and trastuzumab to chemotherapy led to significant improvements in disease-free and overall-survival, In the article that accompanies this podcast, Rimawi and colleagues were interested in exploring if adding pertuzumab to trastuzumab and hormonal therapy could offer additional benefits.  The PERTAIN study was a multicenter phase 2 trial that  enrolled 258 patients with locally-advanced or metastatic hormone-receptor positive, HER2-positive breast cancer who had not previously received systemic therapy in the advanced disease setting, outside of endocrine therapy, and randomized them to receive trastuzumab plus an aromatase inhibitor or trastuzumab plus pertuzumab and an aromatase inhibitor.  Patients were allowed to receive induction chemotherapy with a taxane for 18-24 weeks in combination with trastuzumab (with or without pertuzumab) at the treating investigator's discretion; this was decided prior to randomization and patients were stratified by whether or not they had received induction chemotherapy.  The trial demonstrated an improvement in progression free survival from 15.8 months to 18.89 months with the addition of pertuzumab to an aromatase inhibitor and trastuzumab, meeting its primary endpoint.  This improvement in progression free survival was not associated with a significant improvement in objective response rate (63.3 vs 55.7%).  It is important to note that 57% of patients in the trial received induction chemotherapy, and subgroup analyses demonstrated that amongst those who did not receive chemotherapy, the addition of pertuzumab improved progression free survival from 12.45 months to 21.72 months.  In contrast, amongst those who received induction chemotherapy, the median progression free survival was similar for those who received pertuzumab compared to those who did not, 16.89 and 16.85 months respectively.  This group of patients who received induction chemotherapy had more visceral disease and a shorter medial time since initial breast cancer diagnosis.  Grade 3 and 4 adverse events were more common in those patients receiving all three agents (50.4% vs 38.7%) and the most common toxicities were diarrhea, alopecia and nausea. The PERTAIN trial represents the first randomized trial to investigate the addition of pertuzumab to trastuzumab with an aromatase inhibitor and suggests that endocrine therapy with dual anti-HER2 therapy may be a reasonable treatment approach for some patients with hormone-receptor positive, HER2-positive metastatic breast cancer.  There is also data looking at a different dual anti-HER2 therapy approach with endocrine therapy from the phase 3 ALTERNATIVE trial.  This study looked at the benefits of adding lapatinib to an aromatase inhibitor and trastuzumab and demonstrated a 5-month improvement in progression free survival, but no improvement in overall survival.  These studies suggest that upfront endocrine therapy with dual anti-HER2 therapy may offer a novel treatment option for patients that is likely less toxic and associated with a better quality of life than chemotherapy-based treatment.  One must weigh the pluses and minuses of each treatment approach when choosing the appropriate first line therapy for patients.  Endocrine therapy with dual anti-HER2 therapy has not yet been shown to be associated with a survival benefit, and is associated with lower objective response rates than that seen in the CLEOPATRA study, so it may not be the best approach in a patient with significant visceral disease at presentation, but may be an optimal approach in patients with limited tumor burden, or those who are not optimal candidates for chemotherapy.  Work is also ongoing in the PATINA trial to see if adding cdk 4/6 inhibition to endocrine therapy and dual anti-HER2 therapy, after induction chemotherapy, will have even further benefit. This concludes this JCO Podcast.  Thank you for listening.