Androgen Receptor Splice Variant, AR-V7, as a Biomarker of Resistance to Androgen Axis-Targeted Therapies in Advanced Prostate Cancer.

Many therapeutic options are now available for men with metastatic castration-resistant prostate cancer (mCRPC), including next-generation androgen receptor axis-targeted therapies (AATTs), immunotherapy, chemotherapy, and radioisotope therapies. No clear consensus has been reached for the optimal sequencing of treatments for patients with mCRPC, and few well-validated molecular markers exist to guide the treatment decisions for individual patients. The androgen receptor splice variant 7 (AR-V7), a splice variant of the androgen receptor mRNA resulting in the truncation of the ligand-binding domain, has emerged as a biomarker for resistance to AATT. AR-V7 expression in circulating tumor cells has been associated with poor outcomes in patients treated with second- and third-line AATTs. Clinically validated assays are now commercially available for the AR-V7 biomarker. In the present review of the current literature, we have summarized the biology of resistance to AATT, with a focus on the AR-V7; and the clinical studies that have validated AR-V7 expression as a strong independent predictor of a lack of clinical benefit from AATTs. Existing evidence has indicated that patients with AR-V7-positive mCRPC will have better outcomes if treated with taxane chemotherapy regimens rather than additional AATTs.

Bone marrow tolerance during postoperative chemotherapy in colorectal carcinomas.

BACKGROUND: This study seeks to quantify and compare bone marrow tolerance during postoperative chemotherapy therapy between rectal cancer vs. colon cancer patients. During rectal cancer treatment, patients receive neoadjuvant chemoradiation (CRT) irradiation which can exacerbate the hematologic toxicity (HT) via incidental irradiation of the pelvic bone marrow (PBM) during myelosuppressive postoperative chemotherapy. In contrast, colon cancer patients receive the same postoperative myelosuppressive chemotherapy but do not routinely receive preoperative chemoradiation therapy. This comparison will help elucidate the lasting myelosuppressive effects of incidental pelvic bone marrow (PBM) irradiation on rectal cancer patients during neoadjuvant preoperative chemoradiation therapy. METHODS: Rectal cancer patients treated with preoperative CRT followed by postoperative 5-Fluorouracil and oxaliplatin (OxF) chemotherapy (n=35) were compared to colon cancer patients who received only postoperative OxF chemotherapy (n=42). End points were ≥ grade 3 hematologic toxicity (HT3) or hematologic event (HE) defined as ≥ grade 2 HT and a dose reduction in OxF. Wilcoxon rank sum test tested continuous variables and Chi-squared test measured differences in categorical variables. HT3 and HE probability during postoperative chemotherapy was estimated with Kaplan-Meier curves and Cox regression analysis. RESULTS: During OxF chemotherapy, 40.0% (n=14) of rectal cancer patients experienced HT3 compared to 26.1% (n=11) of colon cancer patients (P=0.4). HE was experienced by 48% (n=17) of rectal cancer patients compared to 36% (n=15) of colon cancer patients (P=0.36). Rectal cancer patients were likelier to experience HT3 on multivariable cox regression analysis, controlling for several clinical covariates, with a hazard ratio (HR) of 2.49, [(95% CI: 1.02-6.02), P=0.045] than colon cancer patients. While rectal cancer patients were more likely to experience HE than colon cancer patients on multivariable Cox regression analysis with a HR of 1.8 (95% CI: 0.95-3.75), this only trended in statistical significance, P=0.07. CONCLUSIONS: Rectal cancer patients are more likely than colon cancer patients to experience hematologic toxicities impacting the tolerance of standard of care chemotherapeutics during adjuvant therapy. Focused PBM sparing during radiation therapy for rectal cancer patients may improve tolerance of myelosuppressive chemotherapeutic agents delivered in the postoperative setting.

Long-Term Bone Marrow Suppression During Postoperative Chemotherapy in Rectal Cancer Patients After Preoperative Chemoradiation Therapy.

PURPOSE/OBJECTIVE(S): To quantify ensuing bone marrow (BM) suppression during postoperative chemotherapy resulting from preoperative chemoradiation (CRT) therapy for rectal cancer. METHODS AND MATERIALS: We retrospectively evaluated 35 patients treated with preoperative CRT followed by postoperative 5-Fluorouracil and oxaliplatin (OxF) chemotherapy for locally advanced rectal cancer. The pelvic bone marrow (PBM) was divided into ilium (IBM), lower pelvis (LPBM), and lumbosacrum (LSBM). Dose volume histograms (DVH) measured the mean doses and percentage of BM volume receiving between 5-40 Gy (i.e.: PBM-V5, LPBM-V5). The Wilcoxon signed rank tests evaluated the differences in absolute hematologic nadirs during neoadjuvant vs. adjuvant treatment. Logistic regressions evaluated the association between dosimetric parameters and ≥ grade 3 hematologic toxicity (HT3) and hematologic event (HE) defined as ≥ grade 2 HT and a dose reduction in OxF. Receiver Operator Characteristic (ROC) curves were constructed to determine optimal threshold values leading to HT3. RESULTS: During OxF chemotherapy, 40.0% (n=14) and 48% (n=17) of rectal cancer patients experienced HT3 and HE, respectively. On multivariable logistic regression, increasing pelvic mean dose (PMD) and lower pelvis mean dose (LPMD) along with increasing PBM-V (25-40), LPBM-V25, and LPBM-V40 were significantly associated with HT3 and/or HE during postoperative chemotherapy. Exceeding ≥36.6 Gy to the PMD and ≥32.6 Gy to the LPMD strongly correlated with causing HT3 during postoperative chemotherapy. CONCLUSIONS: Neoadjuvant RT for rectal cancer has lasting effects on the pelvic BM, which are demonstrable during adjuvant OxF. Sparing of the BM during preoperative CRT can aid in reducing significant hematologic adverse events and aid in tolerance of postoperative chemotherapy.

Neuroembolization of metastatic Merkel cell cancer to the face for treatment of Kasabach-Merritt syndrome.

Kasabach-Merritt syndrome is defined as a consumptive thrombocytopenia in the presence of a highly vascular tumor. Multiple treatment options, including transarterial embolization, have been described. We demonstrate that transarterial embolization is a viable option in the treatment of a rapidly progressive and debilitating Merkel cell tumor metastasizing to the head and neck presenting with Kasabach-Merritt syndrome.

Neuroembolization of metastatic Merkel cell cancer to the face for treatment of Kasabach-Merritt syndrome.

Kasabach-Merritt syndrome is defined as a consumptive thrombocytopenia in the presence of a highly vascular tumor. Multiple treatment options, including transarterial embolization, have been described. We demonstrate that transarterial embolization is a viable option in the treatment of a rapidly progressive and debilitating Merkel cell tumor metastasizing to the head and neck presenting with Kasabach-Merritt syndrome.