Tamoxifen or aromatase inhibitors with ovarian function suppression in pre-menopausal stage I-III lobular breast cancer.

While adjuvant treatment with the selective-estrogen receptor modulator (SERM) tamoxifen has been the standard of care for pre-menopausal patients with hormone receptor (HR) positive breast cancer, recent trials showed a benefit of aromatase inhibitors (AI) and ovarian function suppression (OFS) for some patients. The approach to endocrine therapy has not been well studied in pre-menopausal patients with invasive lobular carcinoma (ILC). We identified 202 pre-menopausal patients with HR positive stage I-III ILC in an institutional database. We investigated factors associated with endocrine therapy type and determined changes in systemic therapy from 1990-2021. We evaluated associations between endocrine therapy type and disease-free survival (DFS) with a multivariate Cox proportional hazards model. Of 202 patients, most (69.3%) were prescribed a SERM (99.3% tamoxifen). Those who received an AI had significantly higher stage disease. Over time, use of OFS and AI increased significantly in stage II or III cases (from 0% in 1990 to 56% after 2015 for stage II; from 0% to 80% after 2015 for stage III). Concurrently, adjuvant chemotherapy use significantly decreased in stage II cases (from 67% to 19%). In an exploratory multivariable model, longer duration of AI compared to tamoxifen was associated with significantly improved DFS (HR 0.31; 95% CI 0.11-0.86; p = 0.025). While most pre-menopausal patients received adjuvant tamoxifen, the use of OFS and AIs increased significantly over time. The association between AI use and improved DFS may be consistent with prior randomized trials and warrants further investigation into predictive factors to guide treatment selection.

Successful Breast Conservation After Neoadjuvant Chemotherapy in Lobular Breast Cancer: The Role of Menopausal Status in Response to Treatment.

BACKGROUND: While neoadjuvant chemotherapy (NAC) has been shown to increase rates of breast conservation surgery (BCS) for breast cancer, response rates in invasive lobular carcinoma (ILC) appear lower than other histologic subtypes. Some data suggest higher response rates to NAC in premenopausal versus postmenopausal patients, but this has not been studied in ILC. We evaluated the rates of successful BCS after NAC in patients with ILC stratified by menopausal status. PATIENTS AND METHODS: We analyzed data from a single-institution cohort of 666 patients with stage I-III hormone receptor positive HER-2 negative ILC. We used t-tests, chi-squared tests, and multivariable logistic regression to investigate rates of NAC use, attempted BCS, and associations between NAC and successful BCS by menopausal status. RESULTS: In 217 premenopausal and 449 postmenopausal patients, NAC was used more often in the premenopausal group (15.2% vs. 9.8%, respectively, p = 0.041). Among those who attempted breast conservation (51.3% of pre- and 64.8% of postmenopausal cohorts), NAC was not associated with successful BCS in either group. Interestingly, for postmenopausal patients, receipt of NAC was significantly associated with increased rates of completion mastectomy in those who had positive margins at the first attempt at BCS. CONCLUSION: NAC was not associated with successful BCS in either premenopausal or postmenopausal patients with ILC. Although premenopausal patients were more likely to receive NAC, these data suggest that menopausal status may not be a good predictor of response to chemotherapy. Better predictors of response and more efficacious treatment for patients with ILC are needed.

Predictors of Early Versus Late Recurrence in Invasive Lobular Carcinoma of the Breast: Impact of Local and Systemic Therapy.

BACKGROUND: Invasive lobular carcinoma (ILC) of the breast is known for high risk of late recurrence, yet some patients still recur within 5 years of diagnosis. Determining factors associated with early/late recurrence could help tailor treatment and surveillance strategies. METHODS: Using an institutional database, we evaluated patients with ILC and ≥ 5 years of follow-up or recurrence within 5 years. We used multivariate logistic regression and the Kaplan-Meier method to evaluate which clinicopathologic features and treatment strategies were associated with recurrence < 5 years since diagnosis versus recurrence ≥ 5 years since diagnosis. Additionally, we explored the association between Clinical Treatment Score 5 (CTS5) with early versus late recurrence. RESULTS: Among 513 cases of stage I-III ILC, there were 75 early and 54 late recurrences during a median follow-up period of 9.4 years. Early recurrence was associated with larger tumors (mean 4.2 cm vs. 2.9 cm, p < 0.0001), higher incidence of > 3 positive nodes (32.4% vs. 9.11%, p > 0.0001), and more aggressive tumor biology (low/negative progesterone receptor expression, higher grade, and higher Ki67). Late recurrence was associated with younger age (mean 55.6 vs. 59.2 years, p = 0.037) and elevated body mass index (BMI > 25 kg/m2 in 60.1.0% vs. 45.4%, p = 0.021). Omission of adjuvant endocrine therapy or radiotherapy after lumpectomy conferred increased risk of early rather than late recurrence. CONCLUSION: Factors related to tumor aggressiveness and treatment were associated with early recurrence, whereas patient related factors were related to late recurrence. These data may help guide treatment strategies and surveillance approaches for patients with ILC.

Mentoring Relationships and Gender Inequities in Academic Medicine: Findings From a Multi-Institutional Qualitative Study.

PURPOSE: This study examined how mentoring relationships may reinforce or mitigate gender inequities in academic medicine. METHOD: In-depth, semistructured interviews with medical school faculty members (52 women and 52 men) were conducted at 16 institutions across the United States in 2019. Institutions were recruited using a purposive sampling strategy to seek diversity in geography, ownership (private or public), and prestige. Within institutions, purposive sampling was used to recruit equal numbers of women and men and to seek diversity in degree type (MD, PhD), age, and career stage. A coding scheme was developed through iterative analysis of the interview transcripts. All interview transcripts were then coded with the goal of identifying intersections between mentorship and experiences of and responses to gender inequities. RESULTS: Four key themes at the intersection of mentoring relationships and gender inequities were identified. (1) Both women and men became aware of gender inequities in academic medicine through relationships with women mentors and mentees. (2) Both women and men mentors recognized the challenges their female mentees faced and made deliberate efforts to help them navigate an inequitable environment. (3) Both women and men mentors modeled work-family balance and created family friendly environments for their mentees. (4) Some women, but no men, reported being sexually harassed by mentors. CONCLUSIONS: This study shows that mentoring relationships may be a context in which gender inequities are acknowledged and mitigated. It also shows that mentoring relationships may be a context in which gender inequities, such as sexual harassment, may occur. Sexual harassment in academic medicine has been widely documented, and gender inequity in academic medicine has proved persistent. While mentoring relationships may have the potential to identify and mitigate gender inequities, this study suggests that this potential remains largely unrealized.

Effects of mutating α-tubulin lysine 40 on sensory dendrite development.

Microtubules are essential for neuronal structure and function. Axonal and dendritic microtubules are enriched in post-translational modifications that impact microtubule dynamics, transport and microtubule-associated proteins. Acetylation of α-tubulin lysine 40 (K40) is a prominent and conserved modification of neuronal microtubules. However, the cellular role of microtubule acetylation remains controversial. To resolve how microtubule acetylation might affect neuronal morphogenesis, we mutated endogenous α-tubulin in vivo using a new Drosophila strain that facilitates the rapid knock-in of designer αTub84B alleles (the predominant α-tubulin-encoding gene in flies). Leveraging our new strain, we found that microtubule acetylation, as well as polyglutamylation and (de)tyrosination, is not essential for survival. However, we found that dendrite branch refinement in sensory neurons relies on α-tubulin K40. Mutagenesis of K40 reveals moderate yet significant changes in dendritic lysosome transport, microtubule polymerization and Futsch protein distribution in dendrites but not in axons. Our studies point to an unappreciated role for α-tubulin K40 and acetylation in dendrite morphogenesis. While our results are consistent with the idea that acetylation tunes microtubule function within neurons, they also suggest there may be an acetylation-independent requirement for α-tubulin K40.This article has an associated First Person interview with the first author of the paper.