Integrating Precision Medicine into the Contemporary Management of Gynecologic Cancers.

PURPOSE OF REVIEW: The treatment of patients with advanced gynecologic malignancies remains challenging. Advancements in genomics have led to recognition and development of individualized therapeutic targets. This article reviews the current trends in precision medicine for treatment of gynecologic cancers. RECENT FINDINGS: With the identification of the molecular aberrations inherent to gynecologic malignancies, we have discovered targetable mutations. Specific to ovarian, endometrial and cervical cancers, potential therapeutic targets that have been identified and shown to have benefit include: hormonal therapies, anti-angiogenic agents, poly-ADP-ribose polymerase inhibitors (PARPi), and immunotherapy. The adoption of targeted therapeutics for the treatment of gynecologic cancers has been gradual, but we have started to see the rapid employment of novel targeted agents into clinical trial development, leading to new treatment approvals. However, there are challenges to the universal precision medicine implementation, and future studies need to identify, discover, and validate robust biomarkers with strong prognostic/predictive capabilities.

Cost-effectiveness of niraparib, rucaparib, and olaparib for treatment of platinum-resistant, recurrent ovarian carcinoma.

BACKGROUND: Olaparib was approved on December 19, 2014 by the US FDA as 4th-line therapy (and beyond) for patients with germline BRCA1/2 mutations; rucaparib was approved on December 19, 2016 as 3rd-line therapy (and beyond) for germline or somatic BRCA1/2-mutated recurrent disease. On October 23, 2019, niraparib was approved for treatment of women with damaging mutations in BRCA1/2 or other homologous recombination repair genes who had been treated with three or more prior regimens. We compared the cost-effectiveness of PARPi(s) with intravenous regimens for platinum-resistant disease. METHODS: Median progression-free survival (PFS) and toxicity data from regulatory trials were incorporated in a model which transitioned patients through response, hematologic complications, non-hematologic complications, progression, and death. Using TreeAge Pro 2017, each PARPi(s) was compared separately to non­platinum-based and bevacizumab-containing regimens. Costs of IV drugs, managing toxicities, infusions, and supportive care were estimated using 2017 Medicare data. Incremental cost-effectiveness ratios (ICERs) were calculated and PFS was reported in quality adjusted life months for platinum-resistant populations. RESULTS: Non­platinum-based intravenous chemotherapy was most cost effective ($6,412/PFS-month) compared with bevacizumab-containing regimens ($12,187/PFS-month), niraparib ($18,970/PFS-month), olaparib ($16,327/PFS-month), and rucaparib ($16,637/PFS-month). ICERs for PARPi(s) were 3-3.5× times greater than intravenous non­platinum-based regimens. CONCLUSION: High costs of orally administered PARPi(s) were not mitigated or balanced by costs of infusion and managing toxicities of intravenous regimens typically associated with lower response and shorter median PFS. Balancing modest clinical benefit with costs of novel therapies remains problematic and could widen disparities among those with limited access to care.

A profile on the FoundationFocus CDxBRCA tests.

Introduction: Poly(ADP-ribose) polymerase (PARP) inhibitors, including rucaparib, are the only targeted class of therapeutics approved for recurrent epithelial ovarian carcinoma with a predictive biomarker. Currently, three different PARP inhibitors are approved for either the treatment of ovarian cancer or maintenance of remission following chemotherapy. The Foundation Focus CDxBRCA is an FDA-cleared next-generation sequencing tumor tissue assay that detects somatic and sometimes germline mutations in BRCA1 and BRCA2 genes.Areas covered: The authors discuss the evolution of the ovarian cancer genomic testing landscape relative to PARP inhibition, with a focus on Foundation Focus CDxBRCA and CDxBRCA Loss of Heterozygosity (LOH), the complementary diagnostics (CDx) to rucaparib.Expert opinion: Relatively early in PARP inhibitor development, women with somatic and/or germline mutations in the BRCA1 and BRCA2 genes were found to have higher response rates to PARP inhibitors with longer durability than women who were BRCA wildtype. Other measures of homologous recombination deficiency including LOH have proven to be predictive biomarkers also. Because PARP biomarkers are genomic and complex, co-development of high-performance companion diagnostics was a high priority. The Foundation Focus test began as a next-generation sequencing assay capable of detecting germline (gBRCA) and somatic (sBRCA) mutations that predict response to rucaparib treatment. The addition of LOH to the assay was validated by a clinical trial supporting expansion of the Rucaparib FDA label to include maintenance of chemotherapy response.

Endometrial cancer in the morbidly obese: a review.

PURPOSE OF REVIEW: With a worldwide increase in obesity, there has been an increase in obesity-related diseases. Endometrial cancer is a common cause of cancer for women worldwide. Incidence of endometrial cancer has risen worldwide. Accompanying these patients are risk factors and challenges that may prevent standard of care from being delivered. RECENT FINDINGS: The current article describes recent literature describing surgical approaches to the obese patient and special considerations in this population. This article also reviews bariatric surgery and endometrial cancer as well as new updates in radiation, chemotherapy and hormonal therapy research in the obese population. SUMMARY: The current article reviews therapeutics and surgery in the morbidly obese for the treatment of endometrial cancer.

Rational design for cervical cancer therapeutics: cellular and non-cellular based strategies on the horizon for recurrent, metastatic or refractory cervical cancer.

INTRODUCTION: Though cervical cytology, HPV DNA testing, and pre-invasive disease management has significantly reduced the number of new diagnoses of cervical cancer, women with persistent oncogenic HPV infection are at significant risk for developing invasive cervical cancer. Early stage and locally advanced disease can be cured, but women with advanced or recurrent disease have a very poor prognosis. This underscores the need for different treatment strategies for advanced cervical cancer, the most promising of which are novel therapeutics that target the ability of HPV to overcome host immune tolerance. Areas covered: This review includes new therapies being investigated for the treatment of recurrent, metastatic or refractory cervical cancer, separated into broad categories of cellular and non-cellular based strategies. Expert opinion: Advanced and recurrent cervical cancer has a poor prognosis, prompting investigations into the development of strategies that will eradicate tumor and/or overcome host immunologic tolerance of disease. It is unknown whether it will be these strategies alone or a combination of treatment modalities that will ultimately provide the best outcomes; nevertheless, the new data are promising.

US FDA oncology drug approvals in 2014.

Cancer is a close second to heart disease for cause of death in the USA, and could soon surpass heart disease as the population ages and the incidence of cancer continues to increase. While heart disease can be addressed through behavior modification and education (e.g., smoking cessation, dietary changes, exercises that promote cardiovascular fitness), pharmacology and improved surgical devices and methods, cancer ultimately requires improved and novel drug treatments to bring mortality rates down. In 2014, the US FDA approved 17 drugs and/or drug combinations in 12 disease sites for a total of 19 indications in melanoma, hematologic malignancies, gastrointestinal carcinoma, non-small-cell lung cancer, gynecologic malignancies and lymphoma/lymphoproliferative disorders.