Pathological validation and significance of micrometastasis in sentinel nodes in primary breast cancer

In embracing a multidisciplinary approach to the management of patients with sentinel node biopsy in breast cancer, the pathologist task is to screen sentinel nodes for possible metastasis. The consequences of missing sentinel node micrometastasis can directly influence treatment strategies, and this screening therefore has to be performed with more attention than usual. There is presently great diversity in the histopathological work-up of sentinel nodes, with many centres employing additional techniques such as immunohistochemistry, reverse transcription polymerase chain reaction or flow cytometry in addition to routine haematoxylin and eosin staining. In this review, we address the pathological validation and significance of micrometastasis in sentinel node biopsy in primary breast cancer

Genomic copy number predicts esophageal cancer years before transformation

Summary Recent studies show that aneuploidies and driver gene mutations precede cancer diagnosis by many years1–4. We assess whether these genomic signals can be used for early detection and pre-emptive cancer treatment using the neoplastic precursor lesion Barrett’s esophagus, as an exemplar5. Shallow whole genome sequencing of 777 biopsies, sampled from 88 patients in Barrett’s surveillance over a period of up to 15 years shows that genomic signals can distinguish progressive from stable disease even ten years prior to histopathological transformation. These findings are validated on two independent cohorts of 76 and 248 patients. These methods are low cost and applicable to standard clinical biopsy samples. Compared with current management guidelines based on histopathology and clinical presentation, genomic classification enables earlier treatment for high risk patients as well as reduction of unnecessary treatment and monitoring for patients who are unlikely to develop cancer.The laboratory of R.C.F. is funded by a Core Programme Grant from the Medical Research Council (RG84369). This work was also funded by a United European Gastroenterology Research Prize (RG76026)

Genomic copy number predicts esophageal cancer years before transformation

Summary Recent studies show that aneuploidies and driver gene mutations precede cancer diagnosis by many years1–4. We assess whether these genomic signals can be used for early detection and pre-emptive cancer treatment using the neoplastic precursor lesion Barrett’s esophagus, as an exemplar5. Shallow whole genome sequencing of 777 biopsies, sampled from 88 patients in Barrett’s surveillance over a period of up to 15 years shows that genomic signals can distinguish progressive from stable disease even ten years prior to histopathological transformation. These findings are validated on two independent cohorts of 76 and 248 patients. These methods are low cost and applicable to standard clinical biopsy samples. Compared with current management guidelines based on histopathology and clinical presentation, genomic classification enables earlier treatment for high risk patients as well as reduction of unnecessary treatment and monitoring for patients who are unlikely to develop cancer.The laboratory of R.C.F. is funded by a Core Programme Grant from the Medical Research Council (RG84369). This work was also funded by a United European Gastroenterology Research Prize (RG76026)

Immune activation by DNA damage predicts response to chemotherapy and survival in oesophageal adenocarcinoma

Objective Current strategies to guide selection of neoadjuvant therapy in oesophageal adenocarcinoma (OAC) are inadequate. We assessed the ability of a DNA damage immune response (DDIR) assay to predict response following neoadjuvant chemotherapy in OAC. Design Transcriptional profiling of 273 formalin-fixed paraffin-embedded prechemotherapy endoscopic OAC biopsies was performed. All patients were treated with platinum-based neoadjuvant chemotherapy and resection between 2003 and 2014 at four centres in the Oesophageal Cancer Clinical and Molecular Stratification consortium. CD8 and programmed death ligand 1 (PD-L1) immunohistochemical staining was assessed in matched resection specimens from 126 cases. Kaplan-Meier and Cox proportional hazards regression analysis were applied according to DDIR status for recurrence-free survival (RFS) and overall survival (OS). Results A total of 66 OAC samples (24%) were DDIR positive with the remaining 207 samples (76%) being DDIR negative. DDIR assay positivity was associated with improved RFS (HR: 0.61; 95% CI 0.38 to 0.98; p=0.042) and OS (HR: 0.52; 95% CI 0.31 to 0.88; p=0.015) following multivariate analysis. DDIR-positive patients had a higher pathological response rate (p=0.033), lower nodal burden (p=0.026) and reduced circumferential margin involvement (p=0.007). No difference in OS was observed according to DDIR status in an independent surgery-alone dataset. DDIR-positive OAC tumours were also associated with the presence of CD8+ lymphocytes (intratumoural: p<0.001; stromal: p=0.026) as well as PD-L1 expression (intratumoural: p=0.047; stromal: p=0.025). Conclusion The DDIR assay is strongly predictive of benefit from DNA-damaging neoadjuvant chemotherapy followed by surgical resection and is associated with a proinflammatory microenvironment in OAC