Role of Immunotherapy in Breast Cancer.

The advent of immunotherapy, particularly immune checkpoint inhibitors (ICIs), has revolutionized the treatment of solid tumor malignancies. In breast cancer, the most robust data to date for ICI exist for triple-negative breast cancer (TNBC). Preclinical studies suggested increased antitumoral immune response in patients with TNBC undergoing ICI treatment. Early clinical trials investigated the use of ICI monotherapy in patients with metastatic TNBC with promising results, particularly in the first-line setting and for those patients whose tumors had high programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) expression. Subsequent trials evaluated the use of ICI in combination with conventional chemotherapy to enhance the host immune response. Pembrolizumab combined with chemotherapy in the KEYNOTE-355 study resulted in improved progression-free survival and overall survival benefits for patients with PD-L1 combined positive score > 10 metastatic TNBC. In early-stage disease, two phase III trials demonstrated increased rates of pathologic complete response at the time of surgery with the addition of neoadjuvant ICI to standard chemotherapy. The large KEYNOTE-522 trial showed improved event-free survival with neoadjuvant and adjuvant ICI. Several biomarkers have been identified, which may be predictive of response to ICI therapy including PD-1/PD-L1 expression, tumor mutational burden, tumor-infiltrating lymphocytes, and multigene assays capturing favorable immune cell signatures. For hormone receptor-positive and human epidermal growth factor receptor-positive breast cancer, there are ongoing studies evaluating ICI therapy in combination with chemotherapy and targeted agents. Finally, across all subtypes, several novel immunotherapeutic agents are under investigation including novel ICIs, cancer vaccines, adoptive cellular therapy, and oncolytic viruses.

The dynamic landscape of BRCA1 reversion mutations from indel to SNV in a patient with ovarian cancer treated with PARP-inhibitors and immunotherapy.

BACKGROUND: Reversion mutations of somatic BRCA mutations are an important source of resistance within ovarian cancer. Furthermore, these reversion mutations are known to change over the course of treatment. Better understanding of the mechanisms leading to reversion mutations and the role of serial ctDNA collection in detecting changes to overall landscape of resistance mutations over time is needed to guide treatment in the metastatic setting. METHODS: Here we study a case of metastatic ovarian cancer undergoing multiple lines of treatment with collection of three serial ctDNA samples. These samples were analyzed by Guardant Health next generation sequencing to detect somatic alterations and their associated mutant allele frequency (MAF) as % cfDNA. RESULTS: Analysis of our initial ctDNA collection, taken during PARP-inhibitor therapy, revealed a nonsense BRCA-1 mutation (c. 2563C > T p. Q855∗), consistent with the BRCA 1 somatic mutation detected on tumor tissue analysis. Initial analysis also revealed a reversion mutation (c.2535_2576del) resulting in an in-frame deletion of the somatic BRCA-1 alteration. The second collection, taken while still on PARP-inhibitor therapy, re-demonstrated this indel reversion mutation along with a second indel reversion mutation (c.2546_2587del), again resulting in an in-frame deletion of the somatic BRCA-1 mutation. The final ctDNA, collected upon initiation of immunotherapy, revealed 4 novel SNV reversion mutations (c.2564A > C, c.2564A > T, c.2565G > T, and c.2565G > C). These SNV reversion mutations result in missense amino acid changes rather than insertions or deletions within the BRCA-1 somatic mutation. The previous indel reversion mutations were no longer detected. CONCLUSIONS: This study illustrates the role of serial ctDNA analyses in the detection of resistance mutations and the dynamic nature of reversion mutations with multiple lines of treatment. While other studies have described both indels and SNVs that occur in tandem, a change in the types of reversion mutations detected across changing therapies has never before been described. Further studies regarding the unique selective pressures arising from use of multiple types of therapy is needed to fully explain this phenomenon.

Cosmetics and Cancer: Adverse Event Reports Submitted to the Food and Drug Administration.

There have been numerous controversies surrounding cosmetic products and increased cancer risk. Such controversies include associations between parabens and breast cancer, hair dyes and hematologic malignancies, and talc powders and ovarian cancer. Despite the prominent media coverage and numerous scientific investigations, the majority of these associations currently lack conclusive evidence. In 2016, the US Food and Drug Administration (FDA) made publically available all adverse event reports in Center for Food Safety and Applied Nutrition's Adverse Event Reporting System (CAERS), which includes complaints related to cosmetic products. We mined CAERS for cancer-related reports attributed to cosmetics. Between 2004 and 2017, cancer-related reports caused by cosmetics represented 41% of all adverse events related to cosmetics. This yielded 4427 individual reports of cancer related to a cosmetic product. Of these reports, the FDA redacted the specific product names in 95% of cancer-related reports under the Freedom of Information Act exemptions, most likely due to ongoing legal proceedings. For redacted reports, ovarian cancer reports dominated (n = 3992, 90%), followed by mesothelioma (n = 92, 2%) and malignant neoplasm unspecified (n = 46, 1%). For nonredacted reports, or those reports whose product names were not withheld (n = 218), 70% were related to ovarian cancer attributed to talc powders, followed by skin cancer (11%) and breast cancer (5%) attributed to topical moisturizers. Currently, CAERS is of limited utility, with the available data having been subjected to significant reporter bias and a lack of supportive information such as demographic data, medical history, or concomitant product use. Although the system has promise for safeguarding public health, the future utility of the database requires broader reporting participation and more complete reporting, paired with parallel investments in regulatory science and improved molecular methods.