Abstract PS9-18: Relative risk of various endocrinopathies associated with the use of chemoimmunotherapy for triple-negative breast cancer: A systematic review and meta-analysis
Authors: Jahan Nusrat , Wongsaengsak Sariya , Singal Sakshi , Rehman Shabnam , Hardwicke Fred , Jones Catherine 
Published: February 2021

Background: Chemoimmunotherapy (CPI+C) is an important addition to the triple-negative breast cancer (TNBC) treatment. However, immune checkpoint inhibitors (CPIs) are frequently associated with significant endocrine toxicities. We conducted a systematic review and meta-analysis of phase 3, randomized controlled trials (RCTs) to determine the relative risk of various endocrinopathies associated with use of CPI+C regimens for the treatment of TNBC.

Methods: We conducted a comprehensive search in the PUBMED, MEDLINE, EMBASE, San Antonio Breast Cancer Symposium, and American Society of Clinical Oncology meeting abstracts as per PRISMA guidelines from inception until June 2020. We included phase 3 RCTs used CPI+C in the intervention arm for the treatment of TNBC and reported the number of events for various endocrinopathies. We used the Mantel-Haenszel method and the random effects model to calculate the pooled risk ratio (RR) with a 95% confidence interval (CI). Heterogeneity was tested with the I2 value and Cochran’s Q statistics. An RR of &lt; 1 was considered to be favorable for the CPI+C, and an RR of &gt; 1 was considered to be unfavorable for the CPI+C. A P-value ≤ 0.05 was considered statistically significant.

Results: Two phase 3 RCTs — IMpassion130 and KEYNOTE-522 — were included in the final analysis. The CPI+C arm included 1233 patients, and the placebo-chemotherapy (P+C) arm included 827 patients. While the IMpassion130 was done in unresectable, locally advanced or metastatic TNBC patients at the first-line setting, the KEYNOTE-522 was done in early stage TNBC patients. For the KEYNOTE-522 study, we used data from the neoadjuvant phase, as in the adjuvant phase, only CPI was continued. The number of patients in the adjuvant phase also differed from the neoadjuvant phase which made it difficult to select appropriate denominator for the RR calculation. Some important characteristics of these studies are included in the table 1. The incidence of any-grade hypothyroidism was 15% in the CPI+C arm vs 3.86% in the P+C arm. The pooled RR of any-grade hypothyroidism was 4.03 (95% CI: 2.79-5.82, P &lt; 0.00001, I2 = 0%). The incidence of any-grade hyperthyroidism was 4.54% in the CPI+C arm vs 1.2% in the P+C arm. The pooled RR of any-grade hyperthyroidism was 3.73 (95% CI: 1.89-7.34, P = 0.0001, I2 = 0%). The incidence of any-grade adrenal insufficiency was 1.78% in the CPI+C arm vs 0% in the P+C arm. The pooled RR of any-grade adrenal insufficiency was 12.87 (95% CI: 1.70-97.34, P = 0.01, I2 = 0%). The incidence of type 1 diabetes mellitus was 0.24% in the CPI+C arm vs 0.24% in the P+C arm. The RR for type 1 diabetes mellitus was not significantly different between the arms — RR: 0.91 (95% CI: 0.14-5.96, P = 0.92, I2 = 0%).

Conclusions: The relative risk of hypothyroidism, hyperthyroidism, and adrenal insufficiency were significantly higher with the use chemoimmunotherapy compared to chemotherapy alone in TNBC patients. CPI induced endocrinopathies are often permanent and require long-term treatment. However, treatment discontinuation is not necessary for CPI induced endocrinopathies. A careful monitoring of symptoms and endocrine functions, and initiation of appropriate treatments are crucial to reduce endocrine related morbidities and mortalities in these patients.

Table 1. Characteristics of the included studies.StudyAuthor/Journal/YearSettingCPI+C armP+C armRandomizationNo.of patients (CPI+C)No. of patients (P+C)IMpassion130Schmid/NEJM/2018Advanced TNBCAtezolizumab + nab-paclitaxelPlacebo + nab-paclitaxel1:1452438KEYNOTE-522Schmid/NEJM/2020Stage II and III TNBCPembrolizumab + paclitaxel + carboplatin + adriamycin or epirubicin + cyclophosphamidePlacebo + paclitaxel + carboplatin + adriamycin or epirubicin + cyclophosphamide2:1781389CPI+C: chemoimmunotherapy; NEJM: The New England Journal of Medicine; P+C: placebo + chemotherapy; TNBC: triple-negative breast cancer.

Citation Format: Nusrat Jahan, Sariya Wongsaengsak, Sakshi Singal, Shabnam Rehman, Fred Hardwicke, Catherine Jones. Relative risk of various endocrinopathies associated with the use of chemoimmunotherapy for triple-negative breast cancer: A systematic review and meta-analysis [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-18.