Each year, tens of thousands of researchers, clinical oncologists, and patient advocates descend on San Antonio, TX to learn about some of the most current research findings in breast cancer over the past year.
Nothing presented this year will “move the needle,” but there were some findings worthy of mention. We will share what we found interesting over the coming weeks. Here are several to start this series.
Triple-Negative Breast Cancer
In July, the Food and Drug Administration (FDA) approved pembrolizumab for high-risk, early-stage, triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery based on results of the Keynote-522.
The trial is a study of neoadjuvant pembrolizumab (Keytruda; an immune checkpoint inhibitor) plus chemotherapy followed by nine cycles of adjuvant pembrolizumab versus chemotherapy alone in triple-negative breast cancer. According to updated results shared at the 2021 SABCS, the addition of pembrolizumab to chemotherapy was found to provide an improvement in both pathologic complete response (pCR) following neoadjuvant treatment and event-free survival (EFS) in patients previously untreated for high-risk, early-stage (stage II or stage III), TNBC.
As reported prior to the 2021 SABCS, pCR was improved among patients receiving chemotherapy plus pembrolizumab compared with those receiving chemotherapy plus placebo (64.8% vs. 51.2%). Now, following 36 months of follow-up, we know that EFS—defined as the time from randomization to disease progression that precludes definitive surgery, local or distant recurrence, a second primary cancer, or death from any cause, whichever occurred first—was also improved, regardless of PDL1 status. A total of 84.5% of patients in the chemotherapy-pembrolizumab arm were event-free at 36 months compared with 76.8% of patients in the control arm, with the most common event recorded being distant recurrence. It is important to note that adverse events in this early-stage setting were not insignificant, including some deaths (~0.5% [3 patients] in the neoadjuvant phase; 0.3% [1 patient] in the adjuvant phase) in the pembrolizumab arm of the trial. One very important question that was not answered by this study (because of the study design) is whether patients who have a pCR following neoadjuvant treatment need to continue with adjuvant pembrolizumab. This is important because we know that among patients who have a pCR, regardless of their trial arm, EFS is high (94.4% and 92.5% respectively). Many questions remain about when and in whom to use pembrolizumab to minimize exposure to the risks.
Updated results were also presented for Keynote-355, which looked at pembrolizumab plus chemo versus chemo alone in the first line of treatment for metastatic TNBC. Notably, overall survival (OS) was improved by nearly seven months (23 months in the treatment arm vs 16.1 months in the control arm) in the pembrolizumab treatment arm, but only among patients who expressed PDL1 positive tumors (measured by Combined Positive Score [CPS] >10), with the largest benefit in patients with relatively high PDL1 (CPS>20) expression.
Based on the results of Keynote 522 (pembrolizumab in the early breast cancer setting), the FDA converted the prior accelerated approval of pembrolizumab in combination with chemotherapy for patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) to a regular approval.
Other Breast Cancer Findings
Results from the phase III CCTGMA.32 trial, which examined the role of the diabetes drug metformin on outcomes (e.g., invasive disease-free survival; overall survival, etc.) in early-stage breast cancer were presented. We learned that metformin did not improve outcomes in patients with early-stage breast cancer regardless of hormone receptor status. There was, however, an interesting exploratory finding that metformin may have a beneficial effect in HER2-positive early-stage breast cancer, specifically in the approximately 70% of HER2-positive individuals in the trial who possess a least one C allele of a prespecified ATM-associated single-nucleotide polymorphism (SNP) [this reflects a normal variation in a particular gene]. It is important to note however that this finding requires replication in a prospective study.
Overdiagnosis From Mammographic Screening in the United States
Breast cancer overdiagnosis is the mammographic detection of breast cancers that would not have caused symptoms or other harms in a woman’s remaining lifetime. There are two primary sources of overdiagnosis. One is the detection of non-progressive cancers, and the other is the detection of progressive cancers that would not have become symptomatic before death from a breast cancer unrelated cause. In a study presented at SABCS 2021, investigators from Duke University presented data from a recent analysis of the estimate of overdiagnosis in mammography screening in the United States. The investigators discussed two common approaches that have been used in past studies to estimate overdiagnosis. The first method is called the “excess incidence” approach, which relies on the empirical comparison of cancer incidence in screened vs. unscreened individuals. The second approach is modeling-based and uses estimates of tumor latency from incidence patterns of screened participants and generates overdiagnosis estimates making assumptions about competition from other causes of mortality. The current study employed a modeling approach and used contemporary screening data (2000 – 2018) from the breast cancer surveillance consortium including women 50-74 years of age, assuming biennial screening. The results of this analysis suggested that approximately 15.3% of all screen-detected breast cancers are overdiagnosed, with approximately 6% being non-progressive cancers and 9.3% being progressive cancers that would not have resulted in death before death from another cause. The model estimates of overdiagnosis also varied by screening round with the risk of overdiagnosis at a woman’s first screening beginning at 50 years of age being approximately 11.5% compared with 23.6% for a woman’s last screening at 74 years of age. Thus, according to this model, the risk of overdiagnosis increases with each successive screening a woman undergoes. The model results were similar when assuming annual screening. One question not addressed in the present analysis was what the estimates of overdiagnosis are when you consider screening that begins at age 40 or 45 years. More study will hopefully answer this question.