Management of Diarrhea in Patients with HER2-Positive Breast Cancer Treated with Neratinib: A Case Series and Summary of the Literature.

INTRODUCTION: Neratinib and neratinib-based combinations have demonstrated efficacy for treatment of human epidermal growth factor receptor 2-positive (HER2+) early-stage and metastatic breast cancers. However, diarrhea has been reported as a common adverse event leading to neratinib discontinuation. Results from the CONTROL trial suggest that proactive diarrhea management with antidiarrheal prophylaxis or dose escalation of neratinib from a lower starting dose to the full FDA-approved dose of 240 mg/day can reduce the incidence, duration, and severity of neratinib-associated diarrhea in patients with early-stage breast cancer. Dose escalation has been included in the FDA-approved label for both early-stage and metastatic HER2+ breast cancer since June 2021. CASE SERIES: This series of five cases details real-world clinical implementation of strategies for management of neratinib-induced diarrhea in patients with early-stage and metastatic HER2+ breast cancer, including a patient with a pre-existing gastrointestinal disorder. MANAGEMENT AND OUTCOME: In four of five cases, diarrhea was managed with neratinib dose escalation, and antidiarrheal prophylaxis with loperamide plus colestipol was used in the remaining case. Management of diarrhea allowed all patients to remain on therapy. DISCUSSION: This case series shows that neratinib-associated diarrhea can be managed effectively with neratinib dose escalation from a lower initial starting dose and/or prophylactic antidiarrheal medications in a real-world clinical setting. The findings highlight the importance of patient-provider communication in proactive management of adverse events. Widespread implementation of the strategies described here may improve adherence and thereby clinical outcomes for patients with HER2+ breast cancer treated with neratinib.

Real-World Outcomes of Everolimus and Exemestane for the Treatment of Metastatic Hormone Receptor-Positive Breast Cancer in Patients Previously Treated With CDK4/6 Inhibitors.

PURPOSE: Everolimus with exemestane (EVE+EXE) was FDA-approved to treat metastatic hormone receptor-positive breast cancer (mHRBC) based on BOLERO-2. However, none of those patients received prior CDK4/6 inhibitors. The purpose of this study is to evaluate the efficacy of EVE+EXE in mHRBC after CDK4/6 inhibitors. METHODS: A retrospective review of patients ≥18 years old with mHRBC treated with EVE+EXE, for ≥30 days, at our institution from January 1, 2012, to April 1, 2020 was conducted. Primary objective was to compare progression free survival (PFS) for EVE+EXE between patients with and without prior exposure to CDK4/6 inhibitors. Secondary outcomes included overall survival and safety. RESULTS: 192 patients were included in the study (n = 79, prior CDK4/6 inhibitor use; n = 113, no prior CDK4/6 inhibitor use). Baseline patient characteristics were similar between groups. Greater number of prior therapies before EVE+EXE use increased risk of disease progression (P = .017). Patients with prior CDK4/6 inhibitor use had a lower median PFS of 3.8 months (95% CI: 3.4-4.7) vs. 5.4 months (95% CI: 3.9-6.2) for patients without prior CDK4/6 inhibitor use, with a HR for progression of 1.46 (95% CI: 1.08 to 1.97, P = .013). Overall survival between groups was not significantly different. CONCLUSION: Patients who received a prior CDK4/6 inhibitor had a lower median PFS benefit from EVE+EXE compared to those who did not, without differences in overall survival. Although PFS is expected to decrease with subsequent lines of therapy, it is reasonable to use EVE+EXE after CDK4/6 inhibitors in selected patients, recognizing that additional benefit is modest.

Adrenal-permissive HSD3B1 genetic inheritance and risk of estrogen-driven postmenopausal breast cancer.

BACKGROUNDGenetics of estrogen synthesis and breast cancer risk has been elusive. The 1245A→C missense-encoding polymorphism in HSD3B1, which is common in White populations, is functionally adrenal permissive and increases synthesis of the aromatase substrate androstenedione. We hypothesized that homozygous inheritance of the adrenal-permissive HSD3B1(1245C) is associated with postmenopausal estrogen receptor-positive (ER-positive) breast cancer.METHODSA prospective study of postmenopausal ER-driven breast cancer was done for determination of HSD3B1 and circulating steroids. Validation was performed in 2 other cohorts. Adrenal-permissive genotype frequency was compared between postmenopausal ER-positive breast cancer, the general population, and postmenopausal ER-negative breast cancer.RESULTSProspective and validation studies had 157 and 538 patients, respectively, for the primary analysis of genotype frequency by ER status in White female breast cancer patients who were postmenopausal at diagnosis. The adrenal-permissive genotype frequency in postmenopausal White women with estrogen-driven breast cancer in the prospective cohort was 17.5% (21/120) compared with 5.4% (2/37) for ER-negative breast cancer (P = 0.108) and 9.6% (429/4451) in the general population (P = 0.0077). Adrenal-permissive genotype frequency for estrogen-driven postmenopausal breast cancer was validated using Cambridge and The Cancer Genome Atlas data sets: 14.4% (56/389) compared with 6.0% (9/149) for ER-negative breast cancer (P = 0.007) and the general population (P = 0.005). Circulating androstenedione concentration was higher with the adrenal-permissive genotype (P = 0.03).CONCLUSIONAdrenal-permissive genotype is associated with estrogen-driven postmenopausal breast cancer. These findings link genetic inheritance of endogenous estrogen exposure to estrogen-driven breast cancer.FUNDINGNational Cancer Institute, NIH (R01CA236780, R01CA172382, and P30-CA008748); and Prostate Cancer Foundation Challenge Award.

Invasive Lobular Breast Cancer: Data to Support Surgical Decision Making.

BACKGROUND: Invasive lobular carcinoma (ILC) is thought be a unique entity with higher rates of multifocal/multicentric and bilateral disease. This study aimed to evaluate the true extent of the disease, risk of bilaterality, lymph node involvement, and impact of preoperative imaging to help guide surgical decision making. METHODS: A retrospective analysis identified patients treated for ILC between 2004 and 2017. Clinical staging and pathologic results were compared. Follow-up details including local recurrence, contralateral breast cancer (CBC), and survival outcomes were evaluated. RESULTS: The study identified 692 patients with ILC, including 43 patients (6%) with a diagnosis of CBC and 232 patients (33%) with a diagnosis of multifocal/multicentric disease at presentation. Preoperative magnetic resonance imaging (MRI) led to an identification of additional disease in 20% of the patients. Preoperative MRI resulted in a more accurate prediction of tumor size staging but did not improve the discordance between clinical and pathologic nodal staging. Overall, the rate of imaging occult lymph node disease was 24%. At the 6-year follow-up evaluation, a local recurrence had developed in 2.3%, a CBC in 2.3, and a distant metastasis in 9.4% of the patients. The overall survival rate was 96% at 3 years and 91% at 5 years. CONCLUSIONS: Invasive lobular carcinoma is a distinct subset of cancer that poses a diagnostic staging challenge. The results of this study favor MRI for accurate tumor staging and for improving detection of multicentricity and bilaterality. However, clinicians should be aware of the higher likelihood of occult lymph node involvement with ILC and subsequent early metastasis.

Managing Genitourinary Syndrome of Menopause in Breast Cancer Survivors Receiving Endocrine Therapy.

Patients with breast cancer receiving antiestrogen therapy, specifically aromatase inhibitors, often suffer from vaginal dryness, itching, irritation, dyspareunia, and dysuria, collectively known as genitourinary syndrome of menopause (GSM). GSM can decrease quality of life and is undertreated by oncologists because of fear of cancer recurrence, specifically when considering treatment with vaginal estrogen therapy because of unknown levels of systemic absorption of estradiol. In this article, we review the available literature for treatment of GSM in patients with breast cancer and survivors, including nonhormonal, vaginal hormonal, and systemic hormonal therapy options. First-line treatment includes nonhormonal therapy with vaginal moisturizers, lubricants, and gels. Although initial studies showed significant improvement in symptoms, the US Food and Drug Administration recently issued a warning against CO2 laser therapy for treatment of GSM until additional studies are conducted. In severe or refractory GSM, after discussing risks and benefits of vaginal hormonal therapy, the low-dose 10-µg estradiol-releasing intravaginal tablet or lower-dose 4 µg estrogen vaginal insert and intravaginal dehydroepiandrosterone (prasterone) are options for treatment, because studies show minimal elevation in serum estradiol levels and significant improvement in symptoms. The decision to offer vaginal estrogen therapy must be individualized and made jointly with the patient and her oncologist.