Tumor Immune Microenvironment and Response to Neoadjuvant Chemotherapy in Hormone Receptor/HER2+ Early Stage Breast Cancer.

BACKGROUND: Pathologic response at the time of surgery after neoadjuvant therapy for HER2 positive early breast cancer impacts both prognosis and subsequent adjuvant therapy. Comprehensive descriptions of the tumor microenvironment (TME) in patients with HER2 positive early breast cancer is not well described. We utilized standard stromal pathologist-assessed tumor infiltrating lymphocyte (TIL) quantification, quantitative multiplex immunofluorescence, and RNA-based gene pathway signatures to assess pretreatment TME characteristics associated pathologic complete response in patients with hormone receptor positive, HER2 positive early breast cancer treated in the neoadjuvant setting. METHODS: We utilized standard stromal pathologist-assessed TIL quantification, quantitative multiplex immunofluorescence, and RNA-based gene pathway signatures to assess pretreatment TME characteristics associated pathologic complete response in 28 patients with hormone receptor positive, HER2 positive early breast cancer treated in the neoadjuvant setting. RESULTS: Pathologist-assessed stromal TILs were significantly associated with pathologic complete response (pCR). By quantitative multiplex immunofluorescence, univariate analysis revealed significant increases in CD3+, CD3+CD8-FOXP3-, CD8+ and FOXP3+ T-cell densities as well as increased immune cell aggregates in pCR patients. In subsets of paired pre/post-treatment samples, we observed significant changes in gene expression signatures in non-pCR patients and significant decreases in CD8+ densities after treatment in pCR patients. No RNA based pathway signature was associated with pCR. CONCLUSION: TME characterization HER2 positive breast cancer patients revealed several stromal T-cell densities and immune cell aggregates associated with pCR. These results demonstrate the feasibility of these novel methods in TME evaluation and contribute to ongoing investigations of the TME in HER2+ early breast cancer to identify robust biomarkers to best identify patients eligible for systemic de-escalation strategies.

Clinical trial data and emerging immunotherapeutic strategies: hormone receptor-positive, HER2- negative breast cancer.

While checkpoint inhibitors have been approved in patients with newly metastatic PDL1-positive triple negative breast cancer, similar clinical benefit with immunotherapy alone or in combination with chemotherapy has not been observed in patients with hormone receptor-positive, HER2- negative breast cancer in the metastatic setting. However, in the ISPY2 trial, an increase in pathologic response has been observed with the addition of immunotherapy (± PARP inhibition) to chemotherapy compared to chemotherapy alone in patients with high-risk hormone receptor-positive, HER2- breast cancer. We review strategies to enhance the immunotherapeutic activity in this subtype of breast cancer, including combinations of checkpoint inhibition with chemotherapy, endocrine therapy, PARP inhibitors, HDAC inhibitors, CDK4/6 inhibitors, and radiotherapy. Combinations with agents targeting novel immunotherapeutic targets are also discussed. Though there remains an unmet need for immunotherapy approaches in patients with hormone-receptor positive breast cancer, there are a number of approaches that may lead to increased anti-tumor activity with immunotherapy in this tumor subtype.

Effect of Time to Surgery of Colorectal Liver Metastases on Survival.

PURPOSE: Resection of liver-only colorectal liver metastases (CRLM) with perioperative chemotherapy is potentially curative. Specific primary tumor and liver metastasis characteristics have been validated to estimate the risk of recurrence. We hypothesize that the time interval from diagnosis of CRLM to surgery, or time to surgery (TTS), is clinically prognostic. METHODS: Patients from a prospectively maintained institutional database at a Comprehensive Cancer Center from May 2003 to January 2018 were reviewed. Clinicopathologic, perioperative treatment, and TTS data were collected. TTS was categorized into short (< 3 months), intermediate (3-6 months), and long (> 6 months) intervals. RESULTS: Two hundred eighty-one patients were identified. While overall survival (OS) was similar across TTS, postoperative overall survival (postoperative OS) of long TTS was associated with worse survival, 44 months (95% CI, 34-52) compared to short TTS, 59 months (95% CI, 43-79), and intermediate TTS, 63 months (95% CI, 52-108), both p < 0.01. With regard to long-term OS, intermediate TTS had 5-year OS of 59% and 8-year OS of 43% compared to long TTS (5-year OS 53% and 8-year OS 18%) and short TTS (5-year OS 54% and 8-year OS 29%). Long TTS was negatively associated with postoperative OS on multivariate analysis (HR 1.6, p < 0.01) when adjusting for resection margin, CRLM size, age, and use of postoperative chemotherapy. CONCLUSION: Short and intermediate TTS had similar survival although patients with intermediate TTS may have better odds of long-term OS. While long TTS was associated with worse survival, likely due to higher disease burden, long-term survivors were still observed.

Venous thrombosis in unusual sites: A practical review for the hematologist.

Thrombosis of unusual venous sites encompasses a large part of consultative hematology and is encountered routinely by practicing hematologists. Contrary to the more commonly encountered lower extremity venous thrombosis and common cardiovascular disorders, the various thromboses outlined in this review have unique presentations, pathophysiology, workup, and treatments that all hematologists should be aware of. This review attempts to outline the most up to date literature on cerebral, retinal, upper extremity, hepatic, portal, splenic, mesenteric, and renal vein thrombosis, focusing on the incidence, pathophysiology, provoking factors, and current recommended treatments for each type of unusual thrombosis to provide a useful and practical review for the hematologist.

A Phase II Study Alternating Erlotinib With Second-line mFOLFOX6 or FOLFIRI for Metastatic Colorectal Cancer.

BACKGROUND: Based on our pre-clinical data, we hypothesized that sequencing chemotherapy with erlotinib would increase the tumor response rate in patients with metastatic colorectal cancer. PATIENTS AND METHODS: A phase II trial (planned n=58) using second-line therapy for metastatic colorectal cancer with either oxaliplatin-based (mFOLFOX6) or irinotecan-based (FOLFIRI) combination chemotherapy and 100 mg erlotinib daily on days 3-8 after each infusion (days 1 and 2) every 14 days. The primary endpoint was the response rate compared to the historical response rate. RESULTS: The FOLFIRI/erlotinib arm met the pre-specified response rate criteria of at least 10% to expand accrual to the intended sample size. The trial was halted after an interim safety analysis (n=11) due to excess grade 3 neutropenia, dose reductions and treatment delays. Grade 3 or 4 neutropenia was observed in 64% of patients. The response rate was 18%. CONCLUSION: In second-line treatment for metastatic colorectal cancer, mFOLFOX6 or FOLFIRI with erlotinib in a sequence-dependent fashion is not feasible despite potential promising activity.