School-Level Efforts to Address Sexual Health and Risky Sexual Behavior Among Students in Texas Alternative High Schools.

We compared sexual/reproductive health services and sexuality education topics provided in Texas alternative high schools (AHSs) with the prevalence of sexual risk behaviors among students in AHS. Using cross-sectional data from convenience samples of 14 principals, 14 lead health educators, and 515 students, we calculated descriptive statistics for 20 services and 15 sexuality education topics provided by AHSs and seven sexual risk behaviors among students in AHS. AHSs provided few sexual/reproductive health services and limited educational content, despite high levels of sexual risk taking among students. For example, no AHSs taught students about proper condom use, yet 84% of students have had sex. Findings provide preliminary evidence of unmet needs for school-based sexual/reproductive health services and comprehensive sexuality education in AHS settings. Future investigation with larger, representative samples is needed to assess the provision of sexual/reproductive health services and sexuality education in AHSs and monitor sexual risk behaviors in the AHS population.

Phase Ib clinical trial of the anti-frizzled antibody vantictumab (OMP-18R5) plus paclitaxel in patients with locally advanced or metastatic HER2-negative breast cancer.

PURPOSE: Vantictumab is a monoclonal antibody that binds to frizzled (FZD) receptors and inhibits canonical WNT signaling. This phase Ib dose escalation study enrolled patients with locally recurrent or metastatic HER2-negative breast cancer who were treated with weekly paclitaxel in combination with escalating doses of vantictumab. METHODS: Patients were enrolled in dose escalation cohorts treated with weekly paclitaxel 90 mg/m2 on days 1, 8 and 15 in combination with vantictumab 3.5-14 mg/kg days 1 and 15 or 3-8 mg/kg day 1 of every 28-day cycle. Primary endpoints were safety, dose-limiting toxicities (DLTs). Secondary endpoints included pharmacokinetics, efficacy and an exploratory biomarker analysis. RESULTS: Forty-eight female patients with a mean age of 54 were enrolled. The majority (66.6%) received prior chemotherapy for recurrent or metastatic disease; 45.8% were hormone receptor (HR)-positive, HER2-negative and 54.2% triple-negative. The most frequent adverse events related to any study treatment were nausea (54.2%), alopecia (52.1%), fatigue (47.9%), and peripheral neuropathy (43.8%). No DLTs occurred; however, 6 patients experienced fractures outside of the DLT window. The overall response rate was 31.3% and the clinical benefit rate was 68.8%. A 6-gene WNT pathway signature showed significant association with progression-free survival (PFS) and overall survival (OS) for the biomarker high versus biomarker low groups (PFS: p = 0.029 and OS: p = 0.00045, respectively). CONCLUSIONS: The combination of vantictumab and weekly paclitaxel was generally well tolerated with promising efficacy; however, the incidence of fractures limits future clinical development of this particular WNT inhibitor in metastatic breast cancer. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov registration: NCT01973309.

The influence of field-based training on caseworker turnover.

Caseworker turnover is a persistent problem for child welfare agencies. This study examines whether field-based pre-service training decreases turnover and examines which organizational factors mediate the effect of training on turnover. We used the population of caseworkers (N = 2365) hired into three caseworker roles during the transition from classroom-based to field-based training in a large U.S. state to compare differences in turnover between classroom-trained and field-trained caseworkers using discrete-time logistic regressions. We find that field-trained conservatorship caseworkers have 39% lower odds of leaving the agency within 18 months of hire compared to similar classroom-trained caseworkers. We examined whether organizational factors explain the effect of training on turnover rates among a sample of surveyed conservatorship caseworkers (72% response rate). We conducted decomposition models to determine the direct and indirect effects of training on turnover. We found that job satisfaction fully mediates the turnover effect and caseworker burnout partially mediates the effect of field-based training on turnover. Though we observed no effect on turnover, field-trained caseworkers in investigations and family-based safety services reported higher job satisfaction. The findings provide the first empirical support for an industry trend toward field-based training.

Who gets a CASA? Selective characteristics of children appointed a CASA advocate.

Prior research examining the effectiveness of Court-Appointed Special Advocates (CASA) as an intervention for improving the outcomes of children in state custody has been hindered by selection bias, because children may be selected to receive CASA representation based on non-random characteristics. Selection bias poses a strong threat to internal validity, and researchers have struggled to isolate the effects of CASA services on child and case outcomes. The present study examines the extent of selection bias in the CASA assignment process over a 2-year period for a full population of foster children in regions served by CASA programs in Texas (N = 32,349), thereby increasing the capacity to control for selection characteristics and supporting causal inference in ongoing studies. This analysis of CASA and state child welfare administrative data examines differences in the baseline child-, family-, and case-level characteristics of children who were appointed CASA representation compared to children who received child welfare services without CASA representation. Mixed-effect logistic regression modeling identifies independent predictors of CASA appointment while controlling for a range of factors and accounting for data clustering in the selection process. Findings indicate that CASA cases in this population have indicators of greater complexity and severity compared to their non-CASA counterparts. By empirically identifying the factors that predict assignment to CASA at the population level, this study lays the foundation for an advanced quasi-experimental outcome evaluation to examine CASA's effectiveness at improving child and case outcomes while minimizing the influence of selection bias.

Effect of a Scalp Cooling Device on Alopecia in Women Undergoing Chemotherapy for Breast Cancer: The SCALP Randomized Clinical Trial.

Importance: Chemotherapy may induce alopecia. Although scalp cooling devices have been used to prevent this alopecia, efficacy has not been assessed in a randomized clinical trial. Objectives: To assess whether a scalp cooling device is effective at reducing chemotherapy-induced alopecia and to assess adverse treatment effects. Design, Setting, and Participants: Multicenter randomized clinical trial of women with breast cancer undergoing chemotherapy. Patients were enrolled from December 9, 2013, to September 30, 2016. One interim analysis was planned to allow the study to stop early for efficacy. Data reported are from the interim analysis. This study was conducted at 7 sites in the United States, and 182 women with breast cancer requiring chemotherapy were enrolled and randomized. Interventions: Participants were randomized to scalp cooling (n = 119) or control (n = 63). Scalp cooling was done using a scalp cooling device. Main Outcomes and Measures: The primary efficacy end points were successful hair preservation assessed using the Common Terminology Criteria for Adverse Events version 4.0 scale (grade 0 [no hair loss] or grade 1 [<50% hair loss not requiring a wig] were considered to have hair preservation) at the end of 4 cycles of chemotherapy by a clinician unaware of treatment assignment, and device safety. Secondary end points included wig use and scores on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, Hospital Anxiety and Depression Scale, and a summary scale of the Body Image Scale. Results: At the time of the interim analysis, 142 participants were evaluable. The mean (SD) age of the patients was 52.6 (10.1) years; 36% (n = 51) received anthracycline-based chemotherapy and 64% (n = 91) received taxane-based chemotherapy. Successful hair preservation was found in 48 of 95 women with cooling (50.5%; 95% CI, 40.7%-60.4%) compared with 0 of 47 women in the control group (0%; 95% CI, 0%-7.6%) (success rate difference, 50.5%; 95% CI, 40.5%-60.6%). Because the 1-tailed P value from the Fisher exact test was <.001, which crossed the superiority boundary (P = .0061), the data and safety monitoring board recommended study termination on September 26, 2016. There were no statistically significant differences in changes in any of the scales of quality of life from baseline to chemotherapy cycle 4 among the scalp cooling and control groups. Only adverse events related to device use were collected; 54 adverse events were reported in the cooling group, all grades 1 and 2. There were no serious adverse device events. Conclusions and Relevance: Among women with stage I to II breast cancer receiving chemotherapy with a taxane, anthracycline, or both, those who underwent scalp cooling were significantly more likely to have less than 50% hair loss after the fourth chemotherapy cycle compared with those who received no scalp cooling. Further research is needed to assess longer-term efficacy and adverse effects. Trial Registration: clinicaltrials.gov Identifier: NCT01986140.

Sotatercept (ACE-011) for the treatment of chemotherapy-induced anemia in patients with metastatic breast cancer or advanced or metastatic solid tumors treated with platinum-based chemotherapeutic regimens: results from two phase 2 studies.

PURPOSE: Sotatercept may represent a novel approach to the treatment of chemotherapy-induced anemia (CIA). We report the results from two phase 2 randomized studies examining the use of sotatercept for the treatment of CIA in patients with metastatic cancer. METHODS: In study A011-08, patients with metastatic breast cancer were randomized to 2:2:2:1 to receive sotatercept 0.1, 0.3, or 0.5 mg/kg, or placebo, respectively, every 28 days. In study ACE-011-NSCL-001, patients with solid tumors treated with platinum-based chemotherapy received sotatercept 15 or 30 mg every 42 days. The primary endpoint for both studies was hematopoietic response, defined as a hemoglobin (Hb) increase of ≥1 g/dL from baseline. RESULTS: Both studies were terminated early due to slow patient accrual. Among patients treated with sotatercept in the A011-08 and ACE-011-NSCL-001 studies, more patients achieved a mean Hb increase of ≥1 g/dL in the combined sotatercept 0.3 mg/kg and 15 mg (66.7 %) group and sotatercept 0.5 mg/kg and 30 mg (38.9 %) group versus the sotatercept 0.1 mg/kg (0 %) group. No patients achieved a mean Hb increase of ≥1 g/dL in the placebo group. The incidence of treatment-related adverse events (AEs) was low in both studies, and treatment discontinuations due to AEs were uncommon. CONCLUSIONS: Although both studies were terminated early, these results indicate that sotatercept is active and has an acceptable safety profile in the treatment of CIA.

Male Prison Inmates With Gender Dysphoria: When Is Sex Reassignment Surgery Appropriate?

Gender dysphoria (GD), a feeling of persistent discomfort with one's biologic sex or assigned gender, is estimated to be more prevalent in male prison inmates than in nonincarcerated males; there may be 3000-4000 male inmates with GD in prisons in the United States. An increasing number of U.S. prison systems now offer gender dysphoric inmates diagnostic evaluation, psychotherapy, cross-sex hormone therapy, and opportunities, albeit limited, to enact their preferred gender role. Sex reassignment surgery (SRS), however, has not been offered to inmates except in response to litigation. In the first case of its kind, the California Department of Corrections and Rehabilitation recently agreed to provide SRS to an inmate and developed policy guidelines for its future provision. In other recent cases, U.S. courts have ruled that male inmates with GD are entitled to SRS when it is medically necessary. Although these decisions may facilitate the provision of SRS to inmates in the future, many U.S. prison systems will probably remain reluctant to offer SRS unless legally compelled to do so. In this review, we address the medical necessity of SRS for male inmates with GD. We also discuss eligibility criteria and the practical considerations involved in providing SRS to inmates. We conclude by offering recommendations for physicians, mental health professionals, and prison administrators, designed to facilitate provision of SRS to inmates with GD in a manner that provides humane treatment, maximizes the likelihood of successful outcomes, minimizes risk of regret, and generates data that can help inform future decisions.

Iniparib plus chemotherapy in metastatic triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancers have inherent defects in DNA repair, making this cancer a rational target for therapy based on poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition. METHODS: We conducted an open-label, phase 2 study to compare the efficacy and safety of gemcitabine and carboplatin with or without iniparib, a small molecule with PARP-inhibitory activity, in patients with metastatic triple-negative breast cancer. A total of 123 patients were randomly assigned to receive gemcitabine (1000 mg per square meter of body-surface area) and carboplatin (at a dose equivalent to an area under the concentration-time curve of 2) on days 1 and 8--with or without iniparib (at a dose of 5.6 mg per kilogram of body weight) on days 1, 4, 8, and 11--every 21 days. Primary end points were the rate of clinical benefit (i.e., the rate of objective response [complete or partial response] plus the rate of stable disease for ≥6 months) and safety. Additional end points included the rate of objective response, progression-free survival, and overall survival. RESULTS: The addition of iniparib to gemcitabine and carboplatin improved the rate of clinical benefit from 34% to 56% (P=0.01) and the rate of overall response from 32% to 52% (P=0.02). The addition of iniparib also prolonged the median progression-free survival from 3.6 months to 5.9 months (hazard ratio for progression, 0.59; P=0.01) and the median overall survival from 7.7 months to 12.3 months (hazard ratio for death, 0.57; P=0.01). The most frequent grade 3 or 4 adverse events in either treatment group included neutropenia, thrombocytopenia, anemia, fatigue or asthenia, leukopenia, and increased alanine aminotransferase level. No significant difference was seen between the two groups in the rate of adverse events. CONCLUSIONS: The addition of iniparib to chemotherapy improved the clinical benefit and survival of patients with metastatic triple-negative breast cancer without significantly increased toxic effects. On the basis of these results, a phase 3 trial adequately powered to evaluate overall survival and progression-free survival is being conducted. (Funded by BiPar Sciences [now owned by Sanofi-Aventis]; ClinicalTrials.gov number, NCT00540358.).

The transition to parenthood in obstetrics: enhancing prenatal care for 2-generation impact.

Obstetrics, the specialty overseeing infant and parent health before birth, could be expanded to address the interrelated areas of parents' prenatal impact on children's brain development and their own psychosocial needs during a time of immense change and neuroplasticity. Obstetrics is primed for the shift that is happening in pediatrics, which is moving from its traditional focus on physical health to a coordinated, whole-child, 2- or multigeneration approach. Pediatric care now includes developmental screening, parenting education, parent coaching, access to developmental specialists, brain-building caregiving skills, linkages to community resources, and tiered interventions with psychologists. Drawing on decades of developmental origins of health and disease research highlighting the prenatal beginnings of future health and new studies on the transition to parenthood describing adult development from pregnancy to early postpartum, we have proposed that, similar to pediatrics, the integration of education and intervention strategies into the prenatal care ecosystem should be tested for its potential to improve child cognitive and social-emotional development and parental mental health. Pediatric care programs can serve as models of change for the systematic development, testing and, incorporation of new content into prenatal care as universal, first-tier treatment and evidenced-based, triaged interventions according to the level of need. To promote optimal beginnings for the whole family, we have proposed an augmented prenatal care ecosystem that aligns with, and could build on, current major efforts to enhance perinatal care individualization through consideration of medical, social, and structural determinants of health.

Trastuzumab Deruxtecan in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases: A DESTINY-Breast01 Subgroup Analysis.

DESTINY-Breast01 (NCT03248492) evaluated trastuzumab deruxtecan (T-DXd; DS-8201) in patients with heavily pretreated HER2-positive metastatic breast cancer (mBC). We present a subgroup of 24 patients with a history of treated brain metastases (BM), a population with limited treatment options. In patients with BMs, the confirmed objective response rate (cORR) was 58.3% [95% confidence interval (CI), 36.6%-77.9%], and the median progression-free survival (mPFS) was 18.1 months (95% CI, 6.7-18.1 months). In patients without BMs (n = 160), cORR was 61.3% and mPFS was 16.4 months. Eight patients (47.1%) experienced a best overall intracranial response of partial response or complete response. Seven patients (41.2%) had a best percentage change in brain lesion diameter from baseline consistent with stable disease. Two patients (8.3%) with BMs and two (1.3%) without BMs experienced progression in the brain. The safety profile of T-DXd was consistent with previous studies. The durable clinical activity of T-DXd in this population warrants further investigation. SIGNIFICANCE: Advances in treating HER2-positive metastatic breast cancer have greatly improved patient outcomes, but intracranial progression remains an important risk for which few therapeutic options are currently available. T-DXd demonstrated durable efficacy in patients with stable, treated BMs. This article is highlighted in the In This Issue feature, p. 2711.

Partnership Instability, School Readiness, and Gender Disparities.

Trends in family formation during the past several decades have increased children's exposure to mothers' partnership instability, defined as an entrance into or exit from a coresidential union or a dating partnership. Instability, in turn, is associated with negative outcomes for children and adolescents. This study uses data from the Fragile Families and Child Wellbeing Study to examine associations between mothers' partnership instability and children's school readiness, differences between coresidential and dating transitions, and the moderating role of child gender. Mothers' partnership transitions are negatively associated with children's verbal ability and positively associated with boys' behavioral problems at age five. In general, coresidential and dating transitions have similar effects on school readiness. The findings have important implications for our understanding of the growing gender gap in educational attainment.

Phase I Study of Elacestrant (RAD1901), a Novel Selective Estrogen Receptor Degrader, in ER-Positive, HER2-Negative Advanced Breast Cancer.

PURPOSE: This phase I study (RAD1901-005; NCT02338349) evaluated elacestrant, an investigational oral selective estrogen receptor degrader (SERD), in heavily pretreated women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer, including those with estrogen receptor gene alpha (ESR1) mutation. The primary objective was to determine the maximum tolerated dose and/or recommended phase II dose (RP2D). METHODS: The study consisted of a 3 + 3 design (elacestrant capsules) followed by expansion at RP2D (400-mg capsules, then 400-mg tablets) for the evaluation of safety and antitumor activity. Elacestrant was taken once daily until progression or intolerability. RESULTS: Of 57 postmenopausal women enrolled, 50 received RP2D (400 mg once daily): median age, 63 years; median three prior anticancer therapies, including cyclin-dependent kinase 4,6 inhibitors (CDK4/6i; 52%), SERD (52%), and ESR1 mutation (circulating tumor DNA; 50%). No dose-limiting toxicities occurred; the most common adverse events at RP2D (400-mg tablet; n = 24) were nausea (33.3%) and increased blood triglycerides and decreased blood phosphorus (25.0% each). Most adverse events were grade 1-2 in severity. The objective response rate was 19.4% (n = 31 evaluable patients receiving RP2D), 15.0% in patients with prior SERD, 16.7% in patients with prior CDK4/6i, and 33.3% in patients with ESR1 mutation (n = 5/15). The clinical benefit rate (24-week) was 42.6% overall (n = 47 patients receiving RP2D), 56.5% (n = 23, ESR1 mutation), and 30.4% (n = 23, prior CDK4/6i). Elacestrant clinical benefit was associated with decline in ESR1 mutant allele fraction. CONCLUSION: Elacestrant 400 mg orally once daily has an acceptable safety profile and demonstrated single-agent activity with confirmed partial responses in heavily pretreated patients with estrogen receptor-positive metastatic breast cancer. Notably, responses were observed in patients with ESR1 mutation as well as those with prior CDK4/6i and prior SERD. A phase III trial investigating elacestrant versus standard endocrine therapy is ongoing.

The Influence of Union Instability and Union Quality on Children's Aggressive Behavior.

We investigate whether mother's poor union quality attenuates the association between union instability and young children's behavioral adjustment. Using data from three waves of the Fragile Families and Child Wellbeing Study to consider children born to married or cohabiting mothers (N=1,730), we determine that children who have experienced poor union quality between mothers and their partners have higher predicted aggressive behavior scores at age 3, regardless of whether they have experienced union transitions, compared to children who have experienced high-quality, stable unions. Children who have experienced instability in the context of higher-quality unions and relatively less acrimonious dissolutions are similar to children raised in high-quality stable unions in terms of predicted aggressive behavior scores.

"Mom, I'm Pregnant": The Adolescent Pregnancy Reveal.

The pregnancy reveal is conventionally a celebratory occasion, but for a pregnant adolescent, sharing news of a pregnancy, particularly with parents, can be a daunting prospect. Nonetheless, given the importance of social support to pregnant and parenting adolescents' success, the pregnancy reveal is an important step toward making healthy pregnancy decisions. Drawing on data from 27 in-depth interviews with young parents in Texas who were peer educators in an adolescent pregnancy prevention program, we find that adolescents often delay telling parents about a pregnancy. The complex decision-making process they undergo as they consider how and from whom to seek help can be drawn out, sometimes well into the second trimester, potentially delaying prenatal care and other steps necessary for a healthy pregnancy. This finding suggests that the delay and its consequences warrant further research and may have implications for parents' and practitioners' conversations with adolescents about sexual and reproductive health.

The Effect of CASA on Child Welfare Permanency Outcomes.

The present study is the largest and most rigorous study to date on the effects of being appointed a Court Appointed Special Advocate (CASA) on permanency outcomes of children in foster care. The intent-to-treat study accounts for selection bias by applying inverse probability weighting to logistic and sequential logistic regressions in a large sample of children in foster care in the state of Texas (N = 31,754). Overall, children appointed a CASA have significantly lower odds than children without a CASA of achieving permanency. They have lower odds of being reunified, greater odds of being adopted (if not reunified), and lower odds of being placed in permanent kin guardianship (if not reunified or adopted) than children who are not appointed CASA. This study makes an additional contribution by looking beyond the aggregate effect of CASA on permanency by examining the effect of CASA for different age groups and different types of first placement after removal.

The addition of hormone therapy to tamoxifen does not prevent hot flashes in women at high risk for developing breast cancer.

Tamoxifen significantly reduces the risk of developing breast cancer in women at increased-risk. The usefulness of tamoxifen has been limited by its side effect profile, especially its propensity to worsen vasomotor symptoms. Hormone therapy (HT) has long been utilized to reduce vasomotor symptoms in peri- and post-menopausal women. The aim of this study was to compare the incidence of hot flashes, weight gain and other side effects associated with taking tamoxifen alone versus tamoxifen in combination with HT in high-risk women. One hundred eighty high-risk women were enrolled into one of two parallel study cohorts to receive tamoxifen alone (93 women) or tamoxifen with HT (87 women). Women were monitored at baseline, 3 months and then yearly for assessments of menopausal symptoms and toxicities associated with tamoxifen alone versus tamoxifen plus HT. We also assessed for differences in menopausal symptoms and toxicities by type of HT (estrogen vs. estrogen and progestin combination). Hot flash scores increased at 3 months and at 1 year compared with baseline in women on tamoxifen alone as well as for women on HT. Women on tamoxifen with estrogen only replacement had the greatest increase in hot flash scores, although this was not significantly different than the increase seen with tamoxifen alone. About 47% of participants on tamoxifen gained weight and there was a strong trend towards less weight gain in women on the combination of tamoxifen and HT, most pronounced for those on tamoxifen with estrogen alone replacement therapy. The addition of HT to tamoxifen therapy does not ameliorate tamoxifen-induced vasomotor symptoms. Tamoxifen associated weight gain, however, may be lessened by the addition of HT.

Giant malignant phyllodes tumor with metastasis to the brain.

We present the case of a 32-year-old African American woman with a giant malignant phyllodes tumor that metastasized to the lungs and subsequently the brain. Her treatment included six cycles of adjuvant therapy with AIM (Adriamycin®, ifosfamide, and mesna) followed by therapy with gemcitabine and docetaxel. A grand mal seizure led to discovery of a 6 × 5 × 5 cm brain mass which was resected. After resection, the patient developed pulmonary edema, repeat seizure activity, and massive intrathoracic progression before succumbing to her disease. This is an unpredictable and understudied neoplasm that can be aggressive and fatal in rare cases.

The Culture Of Health In Early Care And Education: Workers' Wages, Health, And Job Characteristics.

Little is known about the health of the 2.2 million early care and education (ECE) workers responsible for the care, well-being, and success of the approximately ten million children younger than age six enrolled in ECE, or the extent to which ECE environments and employers play a role in workers' health. The purpose of this analysis was to describe the health of an ECE worker sample by wage and by job and center characteristics and to begin to explore the relationships between these factors and workers' health. Our data indicate that ECE workers earn low wages and experience poor mental well-being and high rates of food insecurity. Lower-wage workers worked at centers with more children enrolled in subsidy programs and were more likely to work at centers that did not offer health insurance, paid sick leave, or parental or family leave. Policies and programs that raised workers' wages or mandated the provision of meals to both children and workers could better support teacher health and the quality of ECE for children. Our results suggest that the culture of health in ECE settings and equity-related outcomes could be improved by helping centers provide support and flexibility to teachers (for example, offsetting workers' benefit costs or reducing teacher-to-child ratios to reduce stress) who are managing their own health in the context of demanding work.

Comutation of PIK3CA and TP53 in Residual Disease After Preoperative Anti-HER2 Therapy in ERBB2 (HER2)-Amplified Early Breast Cancer.

PURPOSE: To identify proteomic and genomic alterations in residual disease (RD) for human epidermal growth factor receptor 2 (HER2)-positive (HER2+) breast cancer (BC) after preoperative trastuzumab (H), lapatinib (L), or both (H+L) in combination with chemotherapy. PATIENTS AND METHODS: Patients with stage II/III HER2+ BC (n = 100) were randomly assigned to preoperative treatment with H versus L 1,250mg versus H+L (L: 750 to 1,000 mg) plus 5-fluorouracil, epirubicin, and cyclophosphamide, followed by weekly paclitaxel. After receiving institutional review board-approved informed consent, targeted next-generation sequencing was performed on 20 patients' formalin-fixed paraffin embedded tumors to characterize genomic alterations across 287 cancer-related genes. Reverse phase protein array (RPPA) analysis was performed on both the baseline biopsy and RD specimens, when available. RESULTS: Two of 20 RD tissues were HER2 negative per next-generation sequencing; one sample had insufficient tissue. Of six pretreatment biopsy specimens, four were comutated with TP53 and PIK3CA. Of 17 HER2+ RD, seven specimens (41%) had PIK3CA mutations always comutated with TP53, and four (24%) also had concurrent CDK12 amplification. Overall, CDK12 amplification was observed in eight of the 17 (47%) HER2+ RD specimens. A total of 12 RD specimens (71%) had TP53 mutations. Although prevalence of individual TP53 and PIK3CA mutations was only modestly higher than published estimates for those in HER2+ primary BCs (55% and 32% for TP53 and PIK3CA, respectively), prevalence of these as comutations appeared higher (41%), compared with less than 10% in several series. On RPPA analysis of the RD tissue with comutations, the strongest Spearman ρ correlations were limited to EGFR and phospho-AKT (ρ, 0.999; P = .019) and phospho-mTOR and phospho-S6 ribosomal protein (ρ, 0.994; P = .048). CONCLUSION: HER2-amplified RD tissue after preoperative H, L, or H+L plus chemotherapy was enriched for PIK3CA and TP53 comutations, and the RD tissue demonstrated activation of EGFR/AKT/mTOR signaling on RPPA.

Randomized phase-II evaluation of letrozole plus dasatinib in hormone receptor positive metastatic breast cancer patients.

The non-receptor tyrosine kinase Src activation plays a role in the malignant progression of breast cancer, including development of endocrine therapy resistance and survival of bone metastases. This study investigated whether adding Src kinase inhibitor dasatinib to aromatase inhibitor (AI) therapy improved outcomes in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer (MBC). Postmenopausal patients with ER-positive, HER2-negative MBC (0-1 prior chemotherapies and no prior AI for MBC) were eligible for this non-comparative, parallel group, phase-II study. Patients were randomized to letrozole (2.5 mg/day PO) alone or with dasatinib (100 mg/day PO). Patients with disease progression on letrozole alone could crossover to dasatinib plus continued letrozole. The primary endpoint was clinical-benefit-rate (CBR; complete response + partial response + stable disease ≥6 months). A total of 120 patients were randomized. The CBR of 71% (95% CI 58-83%) was observed with letrozole + dasatinib versus the projected CBR of the combination of 56%. The CBR of 66% (95% CI 52-77%) with letrozole alone also exceeded the projected CBR of 39% with letrozole alone. The CBR was 23% in the crossover arm of letrozole plus dasatinib in patients progressing on letrozole alone. Median progression-free survival with the combination was 20.1 months and 9.9 months with letrozole alone. Letrozole plus dasatinib was well tolerated, although 26% of patients required dasatinib dose reductions. In this non-comparative phase-II trial, the CBR of 71% and the median PFS of 20.1 months with letrozole + dasatinib are encouraging and suggest that dasatinib may inhibit the emergence of acquired resistance to AI therapy.