Discussion
tumor, breast cancer, toxicity, toxicities, HER2-negative, triple-negative breast cancer, aggressive disease, HER2-negative early-stage breast cancer, hypothyroidism, Hypothyroidism
TUMOR, HYPOTHYROIDISM, BREAST CANCER, ADVERSE EVENTS, TRIPLE-NEGATIVE BREAST CANCER, METASTATIC DISEASE, TYPE 1 DIABETES MELLITUS, REGRESSION, RESIDUAL DISEASE, HYPOTHYROIDISM, HER2-NEGATIVE BREAST CANCER
Neoadjuvant immunotherapy combining systemic immune checkpoint blockade with intralesional oncolytic virotherapy could induce a local antitumor response in breast cancer and result in long-lasting systemic immune responses, preventing the future development of metastatic disease. In this phase Ib clinical trial, the combination of nivolumab and reduced-dose ipilimumab with intralesional T-VEC was found to have local antitumor activity in patients with locally advanced HER2-negative breast cancer. Common adverse events consistent with the toxicity profile of T-VEC, including flu-like symptoms within the first few days of T-VEC administration, were noted in all patients. Despite using reduced-dose ipilimumab, this triple combination resulted in irreversible long-term toxicities in 1 patient with type 1 diabetes mellitus and 3 patients with hypothyroidism. Hypothyroidism with nivolumab and ipilimumab is a significant problem (The current study showed antitumor activity, with 1 patient having a pCR and 3 with evidence of tumor regression without complete response. The 2 patients without a pathologic response to therapy had aggressive disease biology at baseline; both had triple-negative breast cancer and positive nodes at diagnosis, and both had already received neoadjuvant chemotherapy without response. Of note, 4 of the 6 patients enrolled in the trial had clinically residual disease after neoadjuvant chemotherapy, which suggests a more aggressive disease. Of these 4 patients, 1 obtained a pCR; this patient had triple-negative breast cancer with the smallest tumor at baseline (1.5 cm) and was node negative clinically at baseline. This patient had enrolled on this trial because she was diagnosed with a second breast cancer at the young age of 47, and had residual disease after neoadjuvant chemotherapy. While pCR is not as robust of an outcome as OS, pCR has been shown to correlate with disease-free survival in prior breast cancer trials (The recent phase II BELLINI clinical trial evaluating nivolumab and ipilimumab in early-stage triple-negative breast cancer reported a partial radiological response in 7 of 31 (23%) patients after 4 weeks (The major limitation of this trial was the limited number of patients enrolled and the heterogeneity of the patients. The eligibility criteria had been deliberately broad (i.e., any localized breast cancer that was palpable, >1 cm, and HER2-negative) because it was a pilot clinical trial, and because of initial concerns about enrollment as well. Furthermore, the trial was opened in September 2019, immediately prior to the COVID-19 pandemic, which also limited enrollment. The trial was closed in April 2021 due to slow enrollment.While this study was limited to 6 patients, the tumor biopsies revealed several intriguing patterns. Both mIF and bulk RNA-seq analyses revealed increased signals associated with CD8In conclusion, the novel combination of T-VEC with nivolumab and ipilimumab as a neoadjuvant treatment for HER2-negative early-stage breast cancer showed antitumor activity at the cost of irreversible long-term toxicities, with type 1 diabetes mellitus in 1 patient and hypothyroidism in 3 patients. Further studies are needed to determine whether there will be any role for T-VEC in the treatment of breast cancer.