Expert Point of View: Charles L. Shapiro, MD

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The ASCO Post asked Charles L. Shapiro, MD, Professor of Medicine, Director of Translational Breast Cancer Research, and Director of Cancer Survivorship at Icahn School of Medicine at Mount Sinai, New York, for his thoughts on the exploratory analysis of PALOMA-3. He first pointed out that the CDK4/6 inhibitors, used in estrogen receptor–positive disease, so far have provided similar benefits as those seen with trastuzumab in patients with HER2-positive disease in the pivotal trials of 2005: They improve progression-free and overall survival with acceptable side effects.

In the testing of biomarkers to identify which patients do, and do not, benefit from CDK4/6 inhibitors, so far, only the presence of the estrogen receptor has been predictive. “In the PALOMA-3 main trial,1 among the prespecified factors that predicted benefits from fulvestrant in combination with palbociclib were prior sensitivity to endocrine therapy, which clinicians have known for decades (ie, past endocrine sensitivity predicts future endocrine sensitivity),” Dr. ­Shapiro noted.

Charles L. Shapiro, MD

Charles L. Shapiro, MD

Dr. Rugo and colleagues have now presented the results of a post hoc analysis of prior chemotherapy vs no prior chemotherapy in the overall intent-to-treat population and in subsets of patients with endocrine-sensitive vs endocrine-resistant disease.2 They also looked at patients according to their prior use of chemotherapy for advanced disease.

For patients previously untreated with chemotherapy in the metastatic setting, median overall survival was 39.7 months with palbociclib/fulvestrant vs 29.5 months with fulvestrant alone (hazard ratio [HR] = 0.75; 95% confidence interval [CI] = 0.56–1.01). For those who had not received prior chemotherapy and were also endocrine-sensitive, median overall survival was 42.3 months vs 32.1 months, respectively (HR = 0.68; 95% CI = 0.48–0.96).

Words of Caution

“This substantial benefit (a median survival difference of about 10 months) might be real and apparent, but with several caveats,” according to Dr. Shapiro.

“First, the women who received prior chemotherapy had more visceral disease, three or more metastatic disease sites, and three or more prior chemotherapies. Inherently, these factors are adverse predictors for realizing benefit from any therapy, so it is not at all surprising that women treated with prior chemotherapy did have lower survival,” he explained.

“The typical sequencing of treating patients with estrogen receptor–positive metastatic disease—unless there are ‘visceral crises’—is to go through sequential treatments with antiestrogen therapies and hold chemotherapy until the disease becomes endocrine-resistant,” Dr. Shapiro pointed out.

“Second, the analysis was a post hoc subset analysis. ‘Post hoc’ means asking a question and performing an analysis after the trial data are in. Many in the scientific community consider post hoc to be inappropriate and subject to biases,”3 he noted. “Nonetheless, prior chemotherapy lessens the response to subsequent treatment—whether it be chemotherapy or antiestrogen therapy—and [this finding] is probably correct, as it fits with decades of clinical experience.” 

DISCLOSURE: Dr. Shapiro reported no conflicts of interest.


1. Turner NC, Slamon DJ, Ro J, et al: Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med 379:1926-1936, 2018.

2. Rugo H, Cristofanilli M, Loibl S, et al: Predictors of efficacy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: Subgroup analyses of ­PALOMA-3. 2020 European Breast Cancer Conference. Abstract 9. Presented October 3, 2020.

3. Schühlen H: Pre-specified vs post-hoc subgroup analyses: Are we wiser before or after a trial has been performed? Eur Heart J 35:2055-2057, 2014.


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