Toxicity profile of antibody-drug conjugates in breast cancer: practical considerations.

Antibody-drug conjugates (ADCs) represent a novel and evolving class of antineoplastic agents, constituted by monoclonal antibody linked to biologically active drugs, delivering cytotoxic compounds at the tumor site, reducing the likelihood of systemic exposure and toxicity. They are generally well tolerated, nevertheless some predictable adverse reactions need careful monitoring and timely approach. These include neutropenia, nausea and vomiting, alopecia, diarrhea, left ventricular dysfunction, ILD/pneumonitis. The mechanisms leading to drug-associated toxicities are summarized, and prophylaxis protocols and appropriate management strategies are proposed, based on current literature. This review aims to collect the most updated evidence on toxicities potentially occurring during breast cancer treatment with approved or under clinical investigation (advanced stage) ADCs. A focus is dedicated to monitoring protocols and clinical management, aimed at preventing and/or promptly address relevant problems, in order to avoid premature discontinuation or improper dose reduction.

Assessment of Total, PTEN-, and AR-V7+ Circulating Tumor Cell Count by Flow Cytometry in Patients with Metastatic Castration-Resistant Prostate Cancer Receiving Enzalutamide.

INTRODUCTION: Metastatic castration-resistant prostate cancer (mCRPC) is a deadly disease. Enzalutamide is an oral second-generation anti-androgen that is active in mCRPC. Circulating tumor cells (CTC) count correlates with overall survival (OS) in mCRPC, whereas detection of the androgen-receptor splice variant 7 (AR-V7) in CTC predicts poor response to oral second-generation anti-androgens. Also, loss of PTEN (phosphatase and tensin homolog) in CTC is a biomarker of poor prognosis in mCRPC. PATIENTS AND METHODS: In this translational study, we employed flow cytometry to assess total, PTEN-, and AR-V7+ CTC count per 7.5 mL of whole blood in a prospective cohort of patients with mCRPC receiving enzalutamide. RESULTS: CTCs were assessed in a total of 45 men with mCRPC at baseline and at 12 weeks. Overall, CTC, PTEN- CTC, and AR-V7+ CTC detection rate was high, at baseline, with 84.4%, 71.1%, and 51.1% of samples showing at least 1 cell/7.5-mL blood, respectively, and after 3 months, with 93.3%, 64.4%, and 77.7% of samples showing at least 1 cell/7.5-mL blood, respectively. Median radiographic progression-free survival (rPFS) and OS were 6 (95% confidence interval [CI], 5.6-9) and 14.3 (95% CI, 12.8-20.3) months, respectively. Median (interquartile range) total CTC count at baseline was 5 (3; 8), whereas median (interquartile range) PTEN- CTC count was 2 (0; 4) and median (interquartile range) AR-V7+ CTC count was 1 (0; 3). At baseline, ≥ 5 versus < 5 total CTC count was associated with worse rPFS (hazard ratio [HR], 2.35; 95% CI, 1.14-4.84; P= .021) and OS (HR, 3.08; 95% CI, 1.45-6.54; P = .003), whereas ≥ 2 versus < 2 PTEN- CTC count was associated with worse rPFS (HR, 3.96; 95% CI, 1.8-8.72; P= .001) and OS (HR, 2.36; 95% CI, 1.12-5; P= .025). Finally, ≥ 1 versus < 1 AR-V7+ CTC count was also associated with worse rPFS (HR, 5.05; 95% CI, 2.4-10.64; P< .001) and OS (HR, 2.25; 95% CI, 1.1-4.58; P= .026). CONCLUSIONS: Despite multiple limitations, including the small sample size, our preliminary study suggests that assessment of CTC via flow cytometry may provide potentially useful prognostic and predictive information in advanced prostate cancer. Further studies are warranted. Micro-Abstract: In this study, men with metastatic castration-resistant prostate cancer, scheduled to start enzalutamide, were assessed for circulating tumor cell count and molecular characterization (total, PTEN-, and AR-V7+ circulating tumor cell count) by the use of flow cytometry. We found that flow cytometry could be used to enumerate circulating tumor cells, but also to assess molecular biomarkers on their surface.

Palbociclib added to ongoing endocrine therapy for hormone receptor-positive HER2-negative metastatic breast cancer: A case report series.

Palbociclib is a potent cyclin-dependent kinase (CDK)4/6 inhibitor that disrupts cell cycle progression and has been recently approved in combination with an aromatase inhibitor or fulvestrant as first- and second-line treatment in hormone receptor (HR)+, human epidermal growth factor receptor (HER)2- metastatic breast cancer. There is evidence that palbociclib may reverse endocrine therapy resistance and that it may also be added to ongoing endocrine therapy beyond progression to obtain clinical benefit. The aim of the present study was to explore this possibility in 5 patients who received palbociclib + fulvestrant following disease progression while under treatment with fulvestrant alone. The median progression-free survival was not reached during a median follow-up of 25 months, and the most frequent best response was stable disease. Three patients remained under treatment on the last re-evaluation. All patients had highly endocrine-sensitive disease and had previously received fulvestrant for ≥12 months. The hypothesis that a selected subpopulation of patients with HR+/HER2- metastatic breast cancer may benefit from the addition of palbociclib to ongoing endocrine therapy beyond disease progression merits further investigation.

PTEN expression in endometrial hyperplasia and risk of cancer: a systematic review and meta-analysis.

PURPOSE: Rates of progression of endometrial hyperplasia (EH) to endometrial cancer (EC) are highly variable. Among several prognostic markers, PTEN has been recommended by ESMO-ESGO-ESTRO to identify premalignant EH. However, its prognostic accuracy is unclear. Thus, we aimed to assess: (1) the association between PTEN loss in EH and risk of cancer, and (2) the prognostic accuracy of PTEN immunohistochemistry in EH. METHODS: Electronic databases were searched from their inception to June 2018. All studies assessing PTEN immunohistochemistry in EH and the presence of EC on subsequent hysterectomy were included. Odds ratio (OR), sensitivity, specificity, positive and negative predictive value (PPV and NPV), positive and negative likelihood ratio (LR + and LR-) and area under the curve (AUC) on SROC curves were calculated with subgroup analysis (short/long-term; atypical/non-atypical EH). RESULTS: Nine retrospective studies assessing 933 EH were included. PTEN loss in EH was significantly associated with increased risk of EC (OR = 3.32, p = 0.001). The association was significant only on the short term ( < 1 year) (OR = 3.45, p = 0.002) and in atypical EH (OR = 1.89, p = 0.01). For overall analysis and short-term/atypical EH subgroup the prognostic accuracy was low, with sensitivity = 0.58 and 0.68, specificity = 0.60 and 0.48, VPp = 0.41 and 0.54, VPN = 0.75 and 0.63, LR + = 1.80 and 1.37, LR - = 0.62 and 0.56, AUC = 0.687 and 0.721, respectively. CONCLUSION: PTEN loss in EH is a risk factor for EC, but is not reliable in predicting the risk of EC. In atypical EH, PTEN loss is associated with a risk of concurrent EC of over 50%. This information might integrate the patients' informed consent for the choice of treatment (conservative/hysterectomy), especially in borderline cases. In conservative approach, PTEN loss might suggest closer follow-up.