Abstract P5-18-08: The relative risk of various endocrinopathies associated with neoadjuvant chemoimmunotherapy use in early-stage triple-negative breast cancer: A systematic review and meta-analysis
Authors: Jahan Nusrat , Rehman Shabnam , Tijani Lukman 
Published: March 2022

Abstract
Background: Immune checkpoint inhibitors (ICIs) are known to cause various irreversible endocrinopathies. Lately, multiple clinical trials have demonstrated that the addition of ICI to the standard neoadjuvant chemotherapy improves pathological complete response (pCR) rate in high-risk early-stage triple-negative breast cancer (TNBC). The pCR has long been regarded as a surrogate marker of favorable outcomes in early-stage TNBC. This systematic review and meta-analysis attempt to determine the risks of various endocrinopathies associated with neoadjuvant chemoimmunotherapy use in early-stage TNBC. Methods: We conducted a systematic search in the PUBMED, MEDLINE, EMBASE, American Society of Clinical Oncology, and San Antonio Breast Cancer Symposium meeting abstracts as per PRISMA guidelines from inception through May 30th, 2021. Published phase 2 and 3 randomized control trials (RCTs) using neoadjuvant ICI plus chemotherapy (ICI+C) in the intervention arm for early-stage TNBC and reporting the number of events for various endocrinopathies were included in the analyses. We used the Mantel-Haenszel method and random-effects model to calculate the estimated pooled risk ratio (RR) with a 95% confidence interval (CI). Heterogeneity was tested with the I2 value and Cochran’s Q-test. Results: Two phase 3 RCTs (IMpassion031 and KEYNOTE-522) and Two phase 2 RCTs (GeparNuevo and I-SPY2) were included in the final analysis. These RCTs randomized 1,106 patients in the ICI+C arm and 819 patients in the placebo plus chemotherapy (P+C) arm. Some essential characteristics of these trials are included in table 1. The incidence of any grade hypothyroidism was 12.84% in the ICI+C arm versus 3.17% in the P+C arm. The pooled RR of any grade hypothyroidism was 3.63 (95% CI: 1.78-7.43, p = 0.0004, I2 = 28%), which was statistically significant. The incidence of any grade hyperthyroidism was 5.24% in the ICI+C arm versus 0.98% in the P+C arm. The pooled RR of any grade hyperthyroidism was 4.08 (95% CI: 1.94-8.59, p = 0.0002, I2 = 3%), which was statistically significant. The incidence of any grade adrenal insufficiency was 2.66% in the ICI+C arm versus 0.14% in the P+C arm. The pooled RR of any grade adrenal insufficiency was 6.84 (95% CI: 0.43-108.95, p = 0.17, I2 = 62%), which was not significant. The incidence of any grade hypophysitis was 1.45% in the ICI+C arm versus 0.16% in the P+C arm. The pooled RR of any grade hypophysitis was 5.29 (95% CI: 0.96-29.25, p = 0.06, I2 = 0%), which was not significant. The incidence of any grade diabetes mellitus was 0.42% in the ICI+C arm versus 0.18% in the P+C arm. The pooled RR of any grade diabetes mellitus 1.81 (95% CI: 0.24-13.63, p = 0.57, I2 = 0%), which was not statistically significant. Conclusions: The addition of immune checkpoint inhibitors (ICIs) to the standard neoadjuvant chemotherapy significantly increases the risk of any grade hypothyroidism and hyperthyroidism. Although the incidences of adrenal insufficiency, hypophysitis, and diabetes mellitus were numerically higher in the ICI+C arm than the P+C arm, they have not achieved statistical significance, possibly due to the rarity of these events. Careful endocrine functions monitoring and appropriate early interventions are crucial in reducing endocrine-related morbidities and mortalities in these patients.
Table 1.Characteristics of the studies included in the meta-analysisStudyPhaseICI usedC usedNo. of patients (ICI+C)No. of patients (P+C)GaperNuevo2DurvalumabNab-paclitaxel + EC9282I-SPY22PembrolizumabPaclitaxel + AC69181IMpassion0313AtezolizumabNab-paclitaxel + AC164167KEYNOTE-5223PembrolizumabPaclitaxel + carboplatin + AC/EC781389AC: doxorubicin + cyclophosphamide; C: chemotherapy; EC: epirubicin + cyclophosphamide; ICI: immune checkpoint inhibitor; P: placebo
Citation Format: Nusrat Jahan, Shabnam Rehman, Lukman Tijani. The relative risk of various endocrinopathies associated with neoadjuvant chemoimmunotherapy use in early-stage triple-negative breast cancer: A systematic review and meta-analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-08.