Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers.

Pathogenic germline TP53 alterations cause Li-Fraumeni Syndrome (LFS), and breast cancer is the most common cancer in LFS females. We performed first of its kind multimodal analysis of LFS breast cancer (LFS-BC) compared to sporadic premenopausal BC. Nearly all LFS-BC underwent biallelic loss of TP53 with no recurrent oncogenic variants except ERBB2 (HER2) amplification. Compared to sporadic BC, in situ and invasive LFS-BC exhibited a high burden of short amplified aneuploid segments (SAAS). Pro-apoptotic p53 target genes BAX and TP53I3 failed to be up-regulated in LFS-BC as was seen in sporadic BC compared to normal breast tissue. LFS-BC had lower CD8+ T-cell infiltration compared to sporadic BC yet higher levels of proliferating cytotoxic T-cells. Within LFS-BC, progression from in situ to invasive BC was marked by an increase in chromosomal instability with a decrease in proliferating cytotoxic T-cells. Our study uncovers critical events in mutant p53-driven tumorigenesis in breast tissue.

Selection of appropriate biomarkers to monitor effectiveness of ovarian function suppression in pre-menopausal patients with ER+ breast cancer.

Use of gonadotropin-releasing hormone (GnRH) agonists has been widely adopted to provide reversible ovarian function suppression for pre-menopausal breast cancer patients who are also receiving aromatase inhibitor or tamoxifen therapy based on results of 25 randomized trials representing almost 15,000 women demonstrating a survival benefit with this approach. Past clinical trials designed to establish the efficacy of GnRH agonists have monitored testosterone in the prostate cancer setting and estradiol in the breast cancer setting. We explore the merits of various biomarkers including estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) and their utility for informing GnRH agonist treatment decisions in breast cancer. Estradiol remains our biomarker of choice in ensuring adequate ovarian function suppression with GnRH agonist therapy among pre-menopausal women with breast cancer. We recommend future trials to continue to focus on estradiol levels as the primary endpoint, as they have in the past.

A prospective longitudinal analysis of the predictors of amenorrhea after breast cancer chemotherapy: Impact of BRCA pathogenic variants.

BACKGROUND: Better tools for post-chemotherapy amenorrhea risk assessment are needed for fertility preservation decision-making. Our aim was to determine the predictors of amenorrhea risk at 12 and 18 months post-chemotherapy in women with breast cancer. METHODS: 142 women with breast cancer were longitudinally followed for their menstrual changes at 6, 12, and 18 months after the completion of adjuvant chemotherapy with an Anthracycline-Cyclophosphamide-based (AC-based) or Cyclophosphamide-Methotrexate +5-Fluorouracil regimen. Pre- and/or post-chemo AMH levels, age, BMI, tamoxifen use, regimen type, and germline BRCA pathogenic variant (gBRCApv) status were evaluated for the prediction of amenorrhea at 6-18 months. RESULTS: In multivariable-adjusted logistic regression, age (p = 0.03) and AMH (p = 0.03) at 12 months, and gBRCApv status (p = 0.03) at 18 months were significant predictors of amenorrhea (areas under the ROC curve of 0.77 and 0.76, for 12 and 18 months, respectively) among 102 evaluable subjects. An undetectable AMH immediately post-chemotherapy was predictive of amenorrhea with <18 month follow-up. In longitudinal analysis estimating time trends, baseline AMH and gBRCApv status was associated with the risk of amenorrhea over 6-18 months; the AMH >2.0 ng/mL group showed attenuated time-trend risk of amenorrhea versus AMH ≤2.0 group (ratio of ORs = 0.91, 95% CI = 0.86-0.97, p = 0.002), while the gBRCApv + showed a steeper time trend, versus the controls (ratio of ORs = 1.12, 95% CI = 1.04-1.20, p = 0.003). CONCLUSIONS: In addition to the pre- and post-treatment AMH levels, gBRCApv status is a novel potential predictor of amenorrhea at 12 and 18 months after chemotherapy. The higher likelihood of amenorrhea in women gBRCApv suggests that they are more prone to losing their fertility post-chemotherapy.

Contrast-enhanced mammography in the assessment of residual disease after neoadjuvant treatment.

PURPOSE: To investigate the utility of contrast-enhanced mammography (CEM) as an alternative to breast MRI for the evaluation of residual disease after neoadjuvant treatment (NAT). METHODS: This prospective study enrolled consecutive women undergoing NAT for breast cancer from July 2017-July 2019. Breast MRI and CEM exams performed after completion of NAT were read independently by two breast radiologists. Residual disease and lesion size on MRI and CEM recombined (RI) and low-energy images (LEI) were compared. Histopathology was considered the reference standard. Statistical analysis was performed using McNemar's and Leisenring's tests. Multiple comparison adjustment was made using Bonferroni procedure. Lesion sizes were correlated using Kendall's tau coefficient. RESULTS: There were 110 participants with 115 breast cancers. Residual disease (invasive cancer or ductal carcinoma in situ) was detected in 83/115 (72%) lesions on pathology, 71/115 (62%) on MRI, 55/115 (48%) on CEM RI, and 75/115 (65%) on CEM LEI. When using multiple comparison adjustment, no significant differences were detected between MRI combined with CEM LEI and CEM RI combined with CEM LEI, in terms of accuracy (MRI: 77%, CEM: 72%; p ≥ 0.99), sensitivity (MRI: 88%, CEM: 81%; p ≥ 0.99), specificity (MRI: 47%, CEM: 50%; p ≥ 0.99), PPV (MRI: 81%, CEM: 81%; p ≥ 0.99), or NPV (MRI: 60%, CEM: 50%; p ≥ 0.99). Size correlation between pathology and both MRI combined with CEM LEI and CEM RI combined with CEM LEI was moderate: τ = 0. 36 vs 0.33 (p ≥ 0.99). CONCLUSION: Contrast-enhanced mammography is an acceptable alternative to breast MRI for the detection of residual disease after neoadjuvant treatment.

Pregnancy-associated breast cancer: does timing of presentation affect outcome?

PURPOSE: Pregnancy-associated breast cancer (PABC) comprises breast cancer diagnosed during the gestational period or within 12 months postpartum. While the incidence of PABC appears to be increasing, data regarding prognosis remain limited. METHODS: Here we evaluate clinicopathologic features, treatments, and clinical outcomes among women with stage 0-III PABC diagnosed between 1992 and 2020. Comparisons were made between women who were diagnosed with PABC during gestation and those who were diagnosed within 12 months postpartum. RESULTS: A total of 341 women were identified, with a median age of 36 years (range 25-46). The pregnancy group comprised 119 (35%) women, while 222 (65%) women made up the postpartum group. Clinicopathologic features were similar between groups, with most patients being parous and presenting with stage I and II disease. Treatment delays were uncommon, with a median time from histologic diagnosis to treatment of 4 weeks for both groups. Recurrence-free survival was similar between groups: 67% at 10 years for both. While 10-year overall survival appeared higher in the postpartum group (83% versus 78%, p = 0.02), only the presence of nodal metastases was associated with an increased risk of death (hazard ratio 5.61, 95% CI 2.20-14.3, p < 0.001), whereas timing of diagnosis and receptor profile did not reach statistical significance. CONCLUSION: Clinicopathologic features of women with PABC are similar regardless of timing of diagnosis. While 10-year recurrence-free survival is similar between groups, 10-year overall survival is higher among women diagnosed postpartum; however, timing of diagnosis may not be the driving factor in determining survival outcomes.

Shared decision making for patients with breast and gynecologic malignancies undergoing chemotherapy associated with persistent alopecia.

Objective: To assess patient-perceived involvement in shared decision making among those diagnosed with breast or gynecologic malignancies undergoing chemotherapy associated with persistent chemotherapy-induced alopecia (pCIA). We also sought to identify factors that influence shared decision making. Methods: We recruited patients from the Gynecologic Medical Oncology and Breast Medicine Services at a large academic center for this prospective cohort study. All patients were scheduled to start chemotherapy between June 1, 2017 and December 31, 2017. Following medical consultation, including discussion of the risk of pCIA, patients completed the 9-item Shared Decision Making Questionnaire (SDM-Q-9). Clinical and sociodemographic information was also collected. Univariate analysis was used to evaluate SDM-Q-9 total scores and their constituents for all variables. Results: Sixty-one patients completed the survey. The median total SDM-Q-9 score was 95.6 (95% CI: 90-100). Most patients (n = 57, 93%) reported a high level of involvement (SDM-Q-9 total score > 66). There was no difference in total scores between patients with breast compared with gynecologic cancer (P > .05). By individual item, the scores for item Q1 ("My doctor made clear that a decision needs to be made") were significantly lower for Black patients and those with advanced disease (P < .05). Conclusions: Most patients indicated they were adequately involved in shared decision making regarding chemotherapy treatment options and their risk for pCIA. Patients from underrepresented populations and those with advanced disease may benefit from additional support from their clinicians to better address the anticipated psychosocial impacts of pCIA and facilitate the provision of optimal and equitable care.

Fertility Preservation in Young Women with Breast Cancer: Impact on Treatment and Outcomes.

BACKGROUND: The impact of chemotherapy timing on the fertility preservation (FP) decision is poorly understood. Here we evaluate factors associated with FP completion among women age ≤ 45 years with breast cancer who received chemotherapy and consulted with a reproductive endocrinology and infertility (REI) specialist, and report pregnancy and oncologic outcomes. PATIENTS AND METHODS: This retrospective review included all women age ≤ 45 years diagnosed with stage I-III unilateral breast cancer at Memorial Sloan Kettering Cancer Center between 2009 and 2015 who received chemotherapy and consulted with an REI specialist. Clinicopathologic features and factors associated with the decision to undergo FP were analyzed, and comparisons were made with the Wilcoxon rank-sum test, Chi-square test, or Fisher's exact test. Survival curves were constructed using the Kaplan-Meier method. RESULTS: Among the 172 women identified, median age was 34 years (interquartile range 31-37 years). The majority of women were single (n = 99, 57.6%) and nulliparous (n = 134, 77.9%). Most women underwent FP (n = 121, 70.3%). Factors associated with the decision to undergo FP included younger median age (33 vs. 37 years, p < 0.001), having private insurance (p < 0.001), nulliparity (p < 0.001), and referral from Breast Surgery (p = 0.004). Tumor characteristics and treatments were similar between women who underwent FP and those who declined. Overall survival and recurrence-free survival were also similar between groups. Women who underwent FP were more likely to have a biological child after breast cancer treatment. CONCLUSIONS: Women underwent FP at high rates independent of timing of chemotherapy and oncologic factors. FP is associated with having a biological child and does not compromise oncologic outcomes.

Phase 1/2 study of topical submicron particle paclitaxel for cutaneous metastases of breast cancer.

PURPOSE: This Phase 1/2 study evaluated safety and efficacy of a topical submicron particle paclitaxel (SPP) in an anhydrous ointment base (SOR007), primarily in breast cancer patients with cutaneous metastases (CM). METHODS: One of three concentrations of SOR007 SPP (0.15%, 1.0%, or 2.0%) was applied twice daily over an area of 50 cm2 under a 3 + 3 phase 1 design for up to 28 days, with the option for expansion to an additional 28 days at the highest dose under a Phase 2a once safety was established. Efficacy was analyzed by lesion measurements and photographs to determine overall response rate (ORR), complete response (CR), and progression free survival by day 28 or 56. RESULTS: Twenty-three subjects were enrolled, 21 with cutaneous metastases of breast cancer (CMOBC). Four subjects received SOR007 0.15% for a median of 28 days (range = 17-29), three at a dose of 1.0% for a median of 28 days (range = 6-29), and sixteen at 2.0% for a median of  55 days (range = 6-60). All doses were well tolerated, and 19 subjects were evaluable for efficacy. At day 28 across all dose levels, 16% (95% CI 3.4 to 39.6%) of subjects achieved an ORR and another 63% (95% CI 34.9-96.8%) had stable disease (SD). The proportion of patients being progression free at 28 days across all treatments was 79% (95 CI 54-94%). CONCLUSION: Application of SOR007 0.15%, 1.0%, and 2.0% to CM was safe and well tolerated with some reduction in lesion pain, and minimal systemic absorption of paclitaxel. Lesion stabilization was observed in most subjects over the study period. A randomized, placebo-controlled trial to confirm these findings is warranted. GOV IDENTIFIER: NCT03101358.

Timing of Presentation and Outcomes of Women with Stage IV Pregnancy-Associated Breast Cancer (PABC).

BACKGROUND: Pregnancy-associated breast cancer (PABC) and concurrent, or early development of, stage IV disease is uncommon. Given this rarity, and complexities surrounding pregnancy, data are limited regarding PABC treatment and outcomes. We evaluated oncologic, obstetric, and fetal outcomes of women with stage IV PABC in relation to presentation timing and treatment. PATIENTS AND METHODS: Our retrospective review of an institutional database identified women with stage IV PABC from 1998 to 2018. PABC was defined as diagnosis during pregnancy or ≤ 1 year postpartum. Clinicopathologic, treatment, and outcome variables were compared between women diagnosed during pregnancy versus postpartum. RESULTS: We identified 77 women (median age 35 years; interquartile range [IQR] 32-37 years): 51 (66%) in the postpartum group and 26 (34%) in the pregnant group, including 9 with therapeutic or spontaneous abortion. Among 17 women who continued pregnancy, no obstetric or fetal complications were noted. Clinicopathologic and treatment variables did not differ between groups. Of 43 women dead from disease, 15 had triple negative (TN) tumors. Median overall survival (OS) of TN tumors was 14 months (range 5-39 months); OS was associated with hormone receptor-positive and human epidermal growth factor receptor 2 (HER2) positive tumors (p < 0.01). At 31 months (range 0-137 months) median follow-up, the 5-year OS was 34% (95% confidence interval 21-46%), and did not differ among pregnant and postpartum groups (p = 0.2). CONCLUSIONS: Women with stage IV TN PABC had high mortality rates despite multimodality therapy. Timing of presentation did not affect management decisions or OS, even for women who completed pregnancy. Further research to understand PABC biology, focusing on TN tumors, is warranted.

Correspondence Between Clinician Ratings of Vulvovaginal Health and Patient-Reported Sexual Function After Cancer.

BACKGROUND: Tools for diagnosing sexual dysfunction and for tracking outcomes of interest include clinician interviews, physical exam, and patient self-report. Limited work has described relationships among these three sources of information regarding female sexual dysfunction and vulvovaginal health. AIM: We describe correlations among data collected from clinician interviews, clinical gynecological examination, and patient self-report. METHODS: Data are from a single-site, single-arm, prospective trial in 100 postmenopausal patients with a history of breast or endometrial cancer who sought treatment for vulvovaginal symptoms. The trial collected a standardized clinical gynecologic exam, clinician-reported outcome (ClinRO) measures of vulvovaginal dryness and pain, and patient-reported outcome (PRO) measures of sexual function, including PROMIS Sexual Function and Satisfaction (SexFS) lubrication, vaginal discomfort, labial discomfort, and clitoral discomfort and Female Sexual Function Index (FSFI) lubrication and pain. We examined polyserial correlations between measures with bootstrapped 95% confidence intervals from the baseline and 12-14-week timepoints. RESULTS: All of the relationships between the ClinRO variables and the PRO variables were in the expected direction (ie, positive), but the strength of the relationships varied substantially. At 12-14 weeks, there were medium-to-large correlations between ClinRO vaginal dryness and SexFS Lubrication (0.64), ClinRO vulvar dryness and SexFS Lubrication (0.46), ClinRO vulvar discomfort and SexFS Labial Discomfort (0.70), and ClinRO vulvar discomfort and SexFS Clitoral Discomfort (0.43). With one exception, the correlations between the exam variables and the corresponding PRO scores were small (range 0.01-0.27). STRENGTHS & LIMITATIONS: Our study included a comprehensive, standardized gynecologic exam designed specifically to evaluate sexual dysfunction as well as established PRO measures with significant evidence for validity. A limitation of our findings is that the sample size was relatively small, and our sample was restricted to women who received cancer treatments known to have dramatic effects on vulvovaginal tissue quality. CONCLUSION: Patient- and clinician-reported vulvovaginal dryness and discomfort were moderately correlated with each other but not with clinical gynecologic exam findings. Understanding the relationships among these different types of data highlights the distinct contributions of each to understand vulvovaginal tissue quality and patient sexual function after cancer. Flynn KE, Lin L, Carter J, et al. Correspondence Between Clinician Ratings of Vulvovaginal Health and Patient-Reported Sexual Function After Cancer. J Sex Med 2021;18:1768-1774.

Impact of adjuvant chemotherapy or tamoxifen-alone on the ovarian reserve of young women with breast cancer.

PURPOSE: To determine the longitudinal impact of adjuvant chemotherapy and tamoxifen-only treatments on the reproductive potential of women with breast cancer by using a sensitive ovarian reserve marker anti-Mullerian hormone (AMH) as a surrogate. METHODS: One-hundred-and-forty-two women with a primary diagnosis of breast cancer were prospectively followed with serum AMH assessments before the initiation, and 12, 18 and 24 months after the completion of adjuvant chemotherapy or the start of tamoxifen-only treatment. The chemotherapy regimens were classified into Anthracycline-Cyclophosphamide-based (AC-based) and Cyclophosphamide-Methotrexate + 5-Fluorouracil (CMF). Longitudinal data were analyzed by mixed effects model for treatment effects over time, adjusting for baseline age and BMI. RESULTS: Both chemotherapy regimens resulted in significant decline in ovarian reserve compared to the tamoxifen-only treatment (p < 0.0001 either regimen vs. tamoxifen for overall trend). AMH levels sharply declined at 12 months but did not show a significant recovery from 12 to 18 and 18 to 24 months after the completion of AC-based or CMF regimens. The degree of decline did not differ between the two chemotherapy groups (p = 0.53). In contrast, tamoxifen-only treatment did not significantly alter the age-adjusted serum AMH levels over the 24-month follow up. Likewise, the use of adjuvant tamoxifen following AC-based regimens did not affect AMH recovery. CONCLUSIONS: Both AC-based regimens and CMF significantly compromise ovarian reserve, without a recovery beyond 12 months post-chemotherapy. In contrast, tamoxifen-only treatment does not seem to alter ovarian reserve. These data indicate that the commonly used chemotherapy regimens but not the hormonal therapy compromise future reproductive potential.

A single-arm, prospective trial investigating the effectiveness of a non-hormonal vaginal moisturizer containing hyaluronic acid in postmenopausal cancer survivors.

PURPOSE: To assess the feasibility and efficacy of a non-hormonal hyaluronic acid (HLA) vaginal gel in improving vulvovaginal estrogen-deprivation symptoms in postmenopausal women with a history of hormone receptor-positive (HR+) cancer. METHODS: For this single-arm, prospective longitudinal trial, we identified disease-free patients with a history of HR+ breast cancer treated with aromatase inhibitors or HR+ endometrial cancer treated with surgery and postoperative radiation. Participants used HLA daily for the first 2 weeks, and then 3×/week until weeks 12-14; dosage was then increased to 5×/week for non-responders. Vulvovaginal symptoms and pH were assessed at 4 time points (baseline [T1], 4-6 weeks [T2], 12-14 weeks [T3], 22-24 weeks [T4]) with clinical evaluation, the Vaginal Assessment Scale (VAS), Vulvar Assessment Scale (VuAS), Female Sexual Function Index (FSFI), and Menopausal Symptom Checklist (MSCL). RESULTS: Of 101 patients, mean age was 55 years (range, 31-78), 68% (n = 69) were partnered, and 60% (n = 61) were sexually active. In linear mixed models, VAS/VuAS scores significantly improved at all assessment points (all p < 0.001). MSCL scores similarly improved (all p < 0.001). FSFI scores significantly improved from T1 to T2 (p < 0.03), T3 (p < 0.001), and T4 (p < 0.001). Severe vaginal pH (> 6.5) decreased from 26% at T1 to 19% at T4 (p = 0.18). CONCLUSIONS: HLA moisturization improved vulvovaginal health/sexual function of cancer survivors. While HLA administration 1-2×/week is recommended for women in natural menopause, a 3-5×/week schedule appears to be more effective for symptom relief in cancer survivors.

Surgical ovarian suppression for adjuvant treatment in hormone receptor positive breast cancer in premenopausal patients.

OBJECTIVE: Ovarian suppression is recommended to complement endocrine therapy in premenopausal women with breast cancer and high-risk features. It can be achieved by either medical ovarian suppression or therapeutic bilateral salpingo-oophorectomy. Our objective was to evaluate characteristics of patients with stage I-III hormone receptor positive primary breast cancer who underwent bilateral salpingo-oophorectomy at our institution. MATERIALS AND METHODS: Premenopausal women with stage I-III hormone receptor positive primary breast cancer diagnosed between January 2010 and December 2014 were identified from a database. Patients with confirmed BRCA1/2 mutations were excluded. Distribution of characteristics between treatment groups was assessed using χ2 test and univariate logistic regression. A multivariate model was based on factors significant on univariate analysis. RESULTS: Of 2740 women identified, 2018 (74%) received endocrine treatment without ovarian ablation, 516 (19%) received endocrine treatment plus ovarian ablation, and 206 (7.5%) did not receive endocrine treatment. Among patients undergoing ovarian ablation 282/516 (55%) received medical ovarian suppression, while 234 (45%) underwent bilateral salpingo-oophorectomy. By univariate logistic analyses, predictors for ovarian ablation were younger age (OR 0.97), histology (other vs ductal: OR 0.23), lymph node involvement (OR 1.89), higher International Federation of Gynecology and Obstetrics (FIGO) stage (stage II vs I: OR 1.48; stage III vs I: OR 2.86), higher grade (grade 3 vs 1: OR 3.41; grade 2 vs 1: OR 2.99), chemotherapy (OR 1.52), and more recent year of diagnosis (2014 vs 2010; OR 1.713). Only year of diagnosis, stage, and human epidermal growth factor receptor 2 (HER-2) treatment remained significant in the multivariate model. Within the cohort undergoing ovarian ablation, older age (OR 1.05) was associated with therapeutic bilateral salpingo-oophorectomy. Of 234 undergoing bilateral salpingo-oophorectomy, 12 (5%) mild to moderate adverse surgical events were recorded. CONCLUSIONS: Bilateral salpingo-oophorectomy is used frequently as an endocrine ablation strategy. Older age was associated with bilateral salpingo-oophorectomy. Perioperative morbidity was acceptable. Evaluation of long-term effects and quality of life associated with endocrine ablation will help guide patient/provider decision-making.

A phase I safety study of topical calcitriol (BPM31543) for the prevention of chemotherapy-induced alopecia.

PURPOSE: Chemotherapy-induced alopecia (CIA) negatively affects psychosocial health and quality of life (QoL). Currently, there are no approved pharmacologic agents to prevent CIA. Here, we evaluated the safety, tolerability, and potential signal of efficacy of topical calcitriol (BPM31543) on CIA prevention. MATERIALS AND METHODS: This Phase 1 trial included 23 female patients with breast cancer, gynecologic cancer, or sarcomas receiving a taxane-based chemotherapy. Patients received a 3 + 3 dose-escalation regimen at 5, 10, 20, 40, 60, and 80 µg/mL, with 3-6 patients per group. Patients applied topical BPM31543 to the scalp twice a day for 2 weeks prior to chemotherapy and continued until chemotherapy treatment was completed. The maximum tolerated dose (MTD) during first 28 day application was determined. Adverse event (AE) monitoring, pharmacokinetics, blinded photographic assessments, and patient self-assessment were evaluated. RESULTS: Out of 23 patients treated with BPM31543, 8 patients experienced at least 1 treatment-related adverse event (AE). The majority of AEs were mild to moderate in severity. Only 1 patient experienced SAEs (vomiting, nausea, fever, and flank pain) considered treatment related. Alopecia < 50% from baseline was observed in 8 patients at Week 7, and, of which 2 patients had < 50% alopecia maintained at Week 15. There were no detectable effects of topical BPM31543 on serum levels of calcitriol. CONCLUSIONS: BPM31543 applied topically twice daily to the scalp is safe and well tolerated in patients receiving taxane-based chemotherapy. No DLT was observed at up to 80 µg/mL, and MTD was not reached. Based on the data from this trial, BPM31543 represents a promising therapy and warrants further investigation in Phase 2/3 trials.

Does Use of Neoadjuvant Chemotherapy Affect the Decision to Pursue Fertility Preservation Options in Young Women with Breast Cancer?

BACKGROUND: The American Society of Clinical Oncology guidelines recommend early referral to reproductive endocrinology and infertility (REI) specialists for young women diagnosed with breast cancer. Current practice patterns demonstrate an increased utilization of neoadjuvant chemotherapy (NAC). We evaluated premenopausal women with breast cancer after consultation with a Fertility Nurse Specialist (FNS) and determine factors associated with referral to REI specialists. METHODS: This retrospective review included all premenopausal women diagnosed at our institution with stage 0-III unilateral breast cancers between 2009 and 2015 who completed an FNS consultation. Clinicopathologic features and factors associated with referral to REI after FNS consultation were analyzed. RESULTS: A total of 334 women were identified. Median age was 35 years (interquartile range 32-38). The majority of women were single (n = 198, 59.3%) and nulliparous (n = 239, 71.6%). REI referrals were common (n = 237, 71.0%). The Breast Surgery service was the most frequent referring service (n = 194, 58.1%), with significantly more REI referrals compared to Breast Medicine and Genetics services (p = 0.002). Nulliparity was associated with REI referral (p < 0.0001). Adjuvant chemotherapy (p = 0.003) was associated with pursuing REI referral, whereas NAC (p < 0.001) was associated with declining REI referral. CONCLUSIONS: Most women elected to consult with an REI specialist, confirming strong interest in fertility preservation among premenopausal women with breast cancer. However, women receiving NAC more frequently declined referral to REI, suggesting that the need to start NAC may influence decisions regarding fertility preservation. With increasing utilization of NAC, our study supports the need for further counseling and education regarding fertility preservation for women undergoing NAC.

A single-arm clinical trial investigating the effectiveness of a non-hormonal, hyaluronic acid-based vaginal moisturizer in endometrial cancer survivors.

OBJECTIVE: To assess the efficacy of non-hormonal, hyaluronic acid (HLA)-based vaginal gel in improving vulvovaginal estrogen-deprivation symptoms in women with a history of endometrial cancer. METHODS: For this single-arm, prospective, longitudinal trial, we enrolled disease-free women with a history of endometrial cancer who underwent surgery (total hysterectomy) and postoperative radiation. Participants used HLA daily for the first 2 weeks, and then 3×/week until weeks 12-14; dosage was then increased to 5×/week for non-responders. Vulvovaginal symptoms and pH were assessed at 4 time points (baseline [T1]; 4-6 weeks [T2]; 12-14 weeks [T3]; 22-24 weeks [T4]) with clinical evaluation, the Vaginal Assessment Scale (VAS), Vulvar Assessment Scale (VuAS), Female Sexual Function Index (FSFI), and Menopausal Symptom Checklist (MSCL). RESULTS: Of 43 patients, mean age was 59 years (range, 38-78); 54% (23/43) were partnered; and 49% (21/43) were sexually active. VAS, VuAS, MSCL, and SAQ (Sexual Activity Questionnaire) scores significantly improved from baseline to each assessment point (all p < .002). FSFI total mean scores significantly increased from T1 to T2 (p < .05) and from T1 to T4 (p < .03). At T1, 41% (16/39) felt confident about future sexual activity compared to 68% (17/25) at T4 (p = .096). Severely elevated vaginal pH (>6.5) decreased from 30% (13/43) at T1 to 19% (5/26) at T4 (p = .41). CONCLUSION: The HLA-based gel improved vulvovaginal health and sexual function of endometrial cancer survivors in perceived symptoms and clinical exam outcomes. HLA administration 1-2×/week is recommended for women in natural menopause; a 3-5×/week schedule appears more effective for symptom relief in cancer survivors.

Increased chemotherapy-induced ovarian reserve loss in women with germline BRCA mutations due to oocyte deoxyribonucleic acid double strand break repair deficiency.

OBJECTIVE: To assess whether woman who have BRCA mutations (WBM) experience more declines in ovarian reserve after chemotherapy treatment, as it induces oocyte death by deoxyribonucleic acid (DNA) damage, and BRCA mutations result in DNA damage repair deficiency. DESIGN: Longitudinal cohort study. SETTING: Academic centers. PATIENT(S): The 108 evaluable women with breast cancer were stratified into those never tested (negative family history; n = 35) and those negative (n = 59) or positive (n = 14) for a pathogenic BRCA mutation. INTERVENTION(S): Sera were longitudinally obtained before and 12-24 months after chemotherapy treatment, assayed for antimüllerian hormone (AMH), and adjusted for age at sample collection. MAIN OUTCOME MEASURE(S): Ovarian recovery, defined as the geometric mean of the after chemotherapy age-adjusted AMH levels compared with baseline levels. RESULT(S): Compared with the controls, the before chemotherapy treatment AMH levels were 24% and 34% lower in those negative or positive for BRCA mutations, consistent with accelerated ovarian aging in WBM. The WBM had a threefold difference in AMH recovery after chemotherapy treatment (1.6%), when compared with BRCA negative (3.7%) and untested/low risk controls (5.2%). Limiting the analysis to the most common regimen, doxorubicin and cyclophosphamide followed by paclitaxel, showed similar results. These findings were mechanistically confirmed in an in vitro mouse oocyte BRCA knockdown bioassay, which showed that BRCA deficiency results in increased oocyte susceptibility to doxorubicin. CONCLUSION(S): Women who have pathogenic BRCA mutations are more likely to lose ovarian reserve after chemotherapy treatment, suggesting an emphasis on fertility preservation. Furthermore, our findings generate the hypothesis that DNA repair deficiency is a shared mechanism between aging, infertility, and cancer. CLINICAL TRIAL REGISTRATION NUMBER: NCT00823654.

Efficacy and Safety of Gemcitabine With Trastuzumab and Pertuzumab After Prior Pertuzumab-Based Therapy Among Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer: A Phase 2 Clinical Trial.

Importance: Taxanes with trastuzumab and pertuzumab for initial treatment of human epidermal growth factor receptor 2 (ERBB2, formerly HER2)-positive metastatic breast cancer is associated with improved progression-free survival (PFS) and overall survival. While continued use of trastuzumab in therapeutic combinations after disease progression is standard, the efficacy of continuing pertuzumab is unknown. Objective: To evaluate the efficacy and safety of pertuzumab in combination with gemcitabine and trastuzumab after prior treatment with pertuzumab for ERBB2-positive metastatic breast cancer. Design, Setting, and Participants: This is a phase 2 single-arm clinical trial of dual anti-ERBB2 therapy after prior treatment with pertuzumab. The study took place at a single academic center from March 2015 to April 2017 among women with ERBB2-positive metastatic breast cancer, prior pertuzumab-based treatment, and 3 or fewer prior chemotherapy regimens. Data were analyzed between January 2019 and March 2019. Intervention: Treatment consisted of gemcitabine, 1200 mg/m2 (later amended to 1000 mg/m2) on days 1 and 8 every 3 weeks, plus trastuzumab (8-mg/kg loading dose, then 6 mg/kg) and pertuzumab (840-mg loading dose, then 420 mg) once every 3 weeks. Main Outcomes and Measures: The primary end point was 3-month PFS. Based on prior trials, a target rate of 70% or higher was selected as the promising progression-free rate at 3 months. Secondary outcomes included safety, tolerability, and overall survival. Results: A total of 45 patients (median [range] age, 57.1 [31.7-77.2] years) were enrolled; 22 (49%) were treated in the second-line setting, and 23 (51%) were treated in the third-line setting or beyond. Of these, 22 (49%) received prior trastuzumab emtansine (T-DM1). At a median (range) follow-up of 27.6 (8.3-36.0) months, 3-month PFS was 73.3% (95% CI, 61.5%-87.5%). Overall, median PFS was 5.5 months (95% CI, 5.4-8.2 months). Treatment was well tolerated, with no occurrences of febrile neutropenia or symptomatic left ventricular systolic dysfunction. Conclusions and Relevance: In this phase 2 trial, treatment with gemcitabine, trastuzumab, and pertuzumab after prior pertuzumab-based therapy for ERBB2-positive metastatic breast cancer was associated with a 3-month PFS rate of 73.3% and was well tolerated. Continuation of pertuzumab beyond progression was associated with apparent clinical benefit. Trial Registration: ClinicalTrials.gov identifier: NCT02252887.

A randomized phase 2 trial of the efficacy and safety of a novel topical povidone-iodine formulation for Cancer therapy-associated Paronychia.

Purpose Cancer therapy-associated paronychia (CAP) is a frequent adverse event associated with cytotoxic and targeted therapies that may impact dosing of anticancer therapies and patient quality of life (QoL). There are currently no evidence-based management strategies or approved treatments for CAP. Materials and Methods This was a prospective, multicenter, randomized, double-blind, vehicle-controlled phase 2 study that evaluated the efficacy and safety of 6 to 8 weeks of 1% or 2% povidone-iodine (PVP-I) topical solution versus vehicle-control in adult patients with CAP. Patients were randomized to one of three treatment arms administered twice daily: 1% PVP-I (Cohort A), 2% PVP-I (Cohort B), or vehicle-control (Cohort C). The primary endpoint was a two-grade reduction (or reduction to grade 0 if involved nails were grade 1) on the six-point Paronychia Severity Grading (PSG) scale. Secondary endpoints included safety and the effect on QoL and microbiota. Results A total of 102 patients with cancer were randomized to the study. In Cohort A, 83 of 205 (40.5%, P = 0.6059) affected nails met the primary endpoint versus Cohort C. In Cohort B, 88 of 167 (52.7%, P = 0.0063) affected nails met the primary endpoint versus 64 of 169 (37.9%) in Cohort C. Nineteen of 29 patients (65.5%) in Cohort B reported moderately or very painful nails at baseline that decreased to 15 patients (51.7%) at visit 2 and five patients (17.2%) at visit 3. Conclusions Treatment with twice-daily topical 2% PVP-I was safe and resulted in improvement in CAP compared with control. Clinicaltrials.gov identifier: NCT03207906. https://clinicaltrials.gov/ct2/show/NCT03207906.