APOBEC Mutational Signatures in Hormone Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Breast Cancers Are Associated With Poor Outcomes on CDK4/6 Inhibitors and Endocrine Therapy.

PURPOSE: APOBEC mutagenesis underlies somatic evolution and accounts for tumor heterogeneity in several cancers, including breast cancer (BC). In this study, we evaluated the characteristics of a real-world cohort for time-to-treatment discontinuation (TTD) and overall survival on CDK4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET) and immune checkpoint inhibitors. METHODS: Comprehensive genomic profiling results from 29,833 BC samples were analyzed for tumor mutational burden and APOBEC signatures. For clinical outcomes, a deidentified nationwide (United States-based) BC Clinico-Genomic Database (CGDB) was evaluated with log-rank and Cox models. Patients with hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) BC who received first-line ET and CDK4/6i were included. Eligible patients from Mayo Clinic and Duke University were HR+ HER2- BC with sequencing data between September 2013 and July 2020. RESULTS: Of 29,833 samples sequenced, 7.9% were APOBEC+ with a high rate in invasive lobular carcinoma (16.7%) and in metastatic tumors (9.7%) relative to locally biopsied BC (4.3%; P < .001). In CGDB, 857 patients with HR+ HER2- BC received ET plus CDK4/6i in the first line. APOBEC+ patients had significantly shorter TTD on ET plus CDK4/6i than APOBEC- patients, 7.8 (95% CI, 4.3 to 14.6) versus 12.4 months (95% CI, 11.2 to 14.1; hazard ratio, 1.6; 95% CI, 1.03 to 2.39; P = .0036). Clinical benefit to immune checkpoint inhibitors was observed in HR+ HER2-, APOBEC+, tumor mutational burden-high patients, with four of nine CGDB patients (TTD 0.3-11.3 months) and four of six patients in Duke/Mayo cohorts (TTD 0.9-40.5 months) with a TTD of ≥ 3 months. CONCLUSION: APOBEC+ HR+ HER2- patients had shorter TTD on first-line ET plus CDK4/6i relative to APOBEC- patients. Further research is needed to optimize the treatment of APOBEC+ HR+ HER2- BC and to investigate the efficacy of immunotherapeutic strategies in this population.

Health care and female survivors of childhood sexual abuse: health professionals' perspectives.

The present study explored health professionals' experiences with adult survivors of child sexual abuse in New Zealand. Face-to-face, semistructured interviews of up to an hour took place with 13 health professionals. The participants were asked about training, screening practices, their response to disclosures, and advice to other health professionals. A model-transition to ethical practice-emerged from the data, where delivering more sensitive health care to child sexual abuse survivors sits on a continuum from lack of awareness of child sexual abuse to delivery of care where all patients are comfortable. We recommend making sensitive care for all as the standard care of practice and providing training for health professionals on how to deal with disclosures.

Working sensitively with child sexual abuse survivors: what female child sexual abuse survivors want from health professionals.

Adult survivors of child sexual abuse are high users of health and mental health services. Health professionals are well placed to improve health outcomes for them by delivering positive interventions post-abuse. The current study explored female child sexual abuse survivors' opinions on how health professionals could work better with child sexual abuse survivors. Sixty-one women, from 22-65 years old, who had been sexually abused before the age of 16 years, completed postal questionnaires in late 2004. A model was developed to guide the development of knowledge, skills, and practices for working more sensitively with child sexual abuse survivors. The model consisted of six chronological training steps: (1) knowledge on effects of child sexual abuse; (2) establishing the relationship with child sexual abuse survivors; (3) asking about child sexual abuse; (4) responding to disclosure; (5) sensitive provision of medical examinations; and (6) follow-up post examination. A systematic approach to training is proposed to assist with improving delivery of services sensitive to child sexual abuse survivor needs.

Health professionals' responses to disclosure of child sexual abuse history: female child sexual abuse survivors' experiences.

This study reports on a postal questionnaire, conducted in 2004, with female survivors of historic child sexual abuse. The questionnaire explored their experiences of health professionals' responsiveness to disclosure of child sexual abuse history. Of 61 participants, aged between 22 and 65, 69% had disclosed to health professionals. Those who had not disclosed reported that they would have liked to but were not asked about child sexual abuse. Thirty-five percent of participants suggested routine questioning about child sexual abuse. Most participants related a fear of common medical examination procedures to their experience of child sexual abuse, and 64% said this stopped them from attending regular health checks. The current study suggests the development of guidelines for dealing with possible child sexual abuse survivors would be useful for health professionals.

Mental health services and sexual abuse: the need for staff training.

Identification of child abuse by mental health services is important for formulation of the causes of presenting problems and for development of comprehensive treatment plans. A small but growing number of studies suggest, however, that the majority of child sexual abuse cases are not identified by mental health services. A similarly small literature also suggests that abuse survivors are extremely reluctant to spontaneously tell anyone about the abuse, indicating that professionals have a responsibility to ask rather than wait for spontaneous disclosures. The purpose of this study, therefore, was to add to these two bodies of literature with a New Zealand sample. A postal questionnaire was completed by 191 women who had received counselling for childhood sexual abuse. The average amount of time taken to tell anyone about the abuse was 16 years. Only 22% of those who had been in contact with public mental health services had ever been asked about abuse by those services. It was concluded that New Zealand women are reluctant to disclose abuse and that mental health services are, as is the case elsewhere, failing to assist them with this process. The need for staff training is discussed, and an example described.

Therapy for child sexual abuse:women talk about helpful and unhelpful therapy experiences.

Women with histories of childhood sexual abuse (CSA) were asked to describe what was helpful and unhelpful to them in therapy. From 191 completed postal questionnaires, a subsample of 20 participants was interviewed. This paper focuses on three specific areas of therapy raised by interviewees: (1) Establishing a therapeutic relationship; (2) talking about experiences and effects of CSA; and (3) dealing with errors in therapy. Findings suggest that to avoid making serious therapy errors, therapists (1) need special skills to be aware of the dynamics and effects of CSA and of abuse-focused therapy and to deal with abuse-related material, and (2) need to develop an equal and open therapy relationship that includes ongoing consultation with clients about their experiences of therapy. doi:10.1300/J070v15n04_03.