Weighing the Evidence: Variant Classification and Interpretation in Precision Oncology, US Food and Drug Administration Public Workshop-Workshop Proceedings.

PURPOSE: Next-generation sequencing (NGS) oncology panels are becoming integral in hospital and academic settings to guide patient treatment and enrollment in clinical trials. Although NGS technologies have revolutionized decision-making for cancer therapeutics, physicians may face many challenges in parsing and prioritizing NGS-based test results to determine the best course of treatment for individual patients. On January 29, 2018, the US Food and Drug Administration held a public workshop entitled, "Weighing the Evidence: Variant Classification and Interpretation in Precision Oncology." Here, we discuss the presentations and discussion highlights across the four sessions of the workshop. METHODS: The goal of the public workshop was to engage stakeholders and solicit input from experts in precision oncology to discuss the integration of complex NGS data into patient management and regulatory innovation within the precision oncology community. The US Food and Drug Administration gathered representatives from academia, industry, patient advocacy, government, and professional organizations for a series of presentations followed by panel discussions. After the workshop, the transcript and speaker presentation slides were reviewed and summarized for manuscript preparation. RESULTS: Speakers and panelists provided diverse perspectives on the integration of NGS technology into patient care for oncology and on the complexities that surround data interpretation and sharing. Discussions highlighted the challenges with standardization for variant classification while expressing the utility of consensus recommendations among stakeholders in oncology for driving innovation in the era of precision medicine. CONCLUSION: As precision medicine advances, clear communication within the field of precision oncology will be key to creating an environment that facilitates the generation and sharing of data that have value to patients.

Ovarian cancer survivors' acceptance of treatment side effects evolves as goals of care change over the cancer continuum.

OBJECTIVES: Women with ovarian cancer can have long overall survival and goals of treatment change over time from cure to remission to stable disease. We sought to determine whether survivors' acceptance of treatment side effects also changes over the disease continuum. METHODS: Women with ovarian cancer completed an online survey focusing on survivors' goals and priorities. The survey was distributed through survivor networks and social media. RESULTS: Four hundred and thirty-four women visited the survey website and 328 (76%) completed the survey. Among participants, 141 (43%) identified themselves as having ever recurred, 119 (36%) were undergoing treatment at the time of survey completion and 86 (26%) had received four or more chemotherapy regimens. Respondents' goals of care were cure for 115 women (35%), remission for 156 (48%) and stable disease for 56 (17%). When asked what was most meaningful, 148 women (45%) reported overall survival, 135 (41%) reported quality of life and 40 (12%) reported progression-free survival. >50% of survivors were willing to tolerate the following symptoms for the goal of cure: fatigue (283, 86%), alopecia (281, 86%), diarrhea (232, 71%), constipation (227, 69%), neuropathy (218, 66%), arthralgia (210, 64%), sexual side effects (201, 61%), reflux symptoms (188, 57%), memory loss (180, 55%), nausea/vomiting (180, 55%), hospitalization for treatment side effects (179, 55%) and pain (169, 52%). The rates of tolerance for most symptoms decreased significantly as the goal of treatment changed from cure to remission to stable disease. CONCLUSIONS: Women with ovarian cancer willingly accept many treatment side effects when the goal of treatment is cure, however become less accepting when the goal is remission and even less so when the goal is stable disease. Physicians and survivors must carefully consider treatment toxicities and quality of life effects when selecting drugs for patients with incurable disease.

The Hippo effector Yorkie controls normal tissue growth by antagonizing scalloped-mediated default repression.

The Hippo tumor suppressor pathway restricts tissue growth by inactivating the transcriptional coactivator Yki. Although Sd has been implicated as a DNA-binding transcription factor partner for Yki and can genetically account for gain-of-function Yki phenotypes, how Yki regulates normal tissue growth remains a long-standing puzzle because Sd, unlike Yki, is dispensable for normal growth in most Drosophila tissues. Here we show that the yki mutant phenotypes in multiple developmental contexts are rescued by inactivation of Sd, suggesting that Sd functions as a default repressor and that Yki promotes normal tissue growth by relieving Sd-mediated default repression. We further identify Tgi as a cofactor involved in Sd's default repressor function and demonstrate that the mammalian ortholog of Tgi potently suppresses the YAP oncoprotein in transgenic mice. These findings fill a major gap in Hippo-mediated transcriptional regulation and open up possibilities for modulating the YAP oncoprotein in cancer and regenerative medicine.

Using Bcr-Abl to examine mechanisms by which abl kinase regulates morphogenesis in Drosophila.

Signaling by the nonreceptor tyrosine kinase Abelson (Abl) plays key roles in normal development, whereas its inappropriate activation helps trigger the development of several forms of leukemia. Abl is best known for its roles in axon guidance, but Abl and its relatives also help regulate embryonic morphogenesis in epithelial tissues. Here, we explore the role of regulation of Abl kinase activity during development. We first compare the subcellular localization of Abl protein and of active Abl, by using a phosphospecific antibody, providing a catalog of places where Abl is activated. Next, we explore the consequences for morphogenesis of overexpressing wild-type Abl or expressing the activated form found in leukemia, Bcr-Abl. We find dose-dependent effects of elevating Abl activity on morphogenetic movements such as head involution and dorsal closure, on cell shape changes, on cell protrusive behavior, and on the organization of the actin cytoskeleton. Most of the effects of Abl activation parallel those caused by reduction in function of its target Enabled. Abl activation leads to changes in Enabled phosphorylation and localization, suggesting a mechanism of action. These data provide new insight into how regulated Abl activity helps direct normal development and into possible biological functions of Bcr-Abl.