HER2-positive breast cancer has long proven to be a clinically distinct class of breast cancers for which several targeted therapies are now available. However, resistance to the treatment associated ...with specific gene expressions or mutations has been observed, revealing the underlying diversity of these cancers. Therefore, understanding the full extent of the HER2-positive disease heterogeneity still remains challenging. Here we carry out an in-depth genomic characterization of 64 HER2-positive breast tumour genomes that exhibit four subgroups, based on the expression data, with distinctive genomic features in terms of somatic mutations, copy-number changes or structural variations. The results suggest that, despite being clinically defined by a specific gene amplification, HER2-positive tumours melt into the whole luminal-basal breast cancer spectrum rather than standing apart. The results also lead to a refined ERBB2 amplicon of 106 kb and show that several cases of amplifications are compatible with a breakage-fusion-bridge mechanism.
We explored, within the EORTC10994 study, the outcomes for patients with molecular apocrine (MA) breast cancer, and defined immunohistochemistry (IHC) as androgen-receptor (AR) positive, oestrogen ...(ER) and progesterone (PR) negative. We also assessed the concordance between IHC and gene expression arrays (GEA) in the identification of MA cancers.
Centrally assessed biopsies for AR, ER, PR, HER2 and Ki67 by IHC were classified into six subtypes: MA, triple-negative (TN) basal-like, luminal A, luminal B HER2 negative, luminal B HER2 positive and "other". The two main objectives were the pCR rates and survival outcomes in the overall MA subtype (and further divided by HER2 status) and the remaining five subtypes.
IHC subtyping was obtained in 846 eligible patients. Ninety-three (11%) tumours were classified as the MA subtype. Both IHC and GEA data were available for 64 patients. In this subset, IHC concordance was 88.3% in identifying MA tumours compared with GEA. Within the MA subtype, pCR was observed in 33.3% of the patients (95% CI: 29.4-43.9) and the 5-year recurrence-free interval was 59.2% (95% CI: 48.2-68.6). Patients with MA and TN basal-like tumours have lower survival outcomes.
Irrespective of their HER2 status, the prognosis for MA tumours remains poor and adjuvant trials evaluating anti-androgens should be considered.
Two-stage hepatectomy for bilobar colorectal cancer liver metastases is potentially curative for selected patients. Histological growth patterns of colorectal liver metastases (desmoplastic, ...replacement, and pushing) have prognostic value. Our aim was to evaluate their association with pathologic response to preoperative treatment, second-stage hepatectomy completion, and survival in patients treated with a curative-intent 2-stage hepatectomy.
In 67 patients planned for 2-stage hepatectomy, colorectal liver metastases resected from the first-stage hepatectomy were retrospectively evaluated for growth patterns and pathologic response according to Tumor Regression Grading, modified Tumor Regression Grading, and Blazer grading. Tumor Regression Grading 1 to 3, modified Tumor Regression Grading 1 to 3, and Blazer 0 and 1 defined good responders.
Desmoplastic growth patterns (GP) were more frequent among good responders (P < .001). Second-stage hepatectomy completion was associated with desmoplastic growth patterns and pathologic response on univariate analysis and multivariable analyses (P = .017 and P = .041, respectively). Median follow-up was 84 months (95% confidence interval: 53.4 not reached). Nondesmoplastic GP patients and nonresponders had a poorer overall survival (hazard ratio = 3.86, 95% confidence interval: 2.11–7.07, P < .001 and hazard ratio = 2.14, 95% confidence interval: 1.19–3.83, P = .009, respectively) on univariate analysis. Nondesmoplastic growth pattern was the only factor associated with a poorer overall survival on multivariable analysis (hazard ratio = 4.17, 95% confidence interval: 1.79–9.74, P < .001). Nondesmoplastic GP was also associated with a poorer recurrence-free survival (hazard ratio = 2.05, 95% confidence interval: 1.13–3.70, P = .017).
Desmoplastic GP could represent a useful morphological marker for early identification of patients who might benefit from 2-stage hepatectomy completion.
Pseudomyxoma peritonei (PMP) is a rare disease characterized by the progressive accumulation of mucinous ascites and peritoneal implants. The optimal treatment for PMP includes the association of ...complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). For patients with a large burdensome disease, the completeness of cytoreduction sometimes requires maximal effort surgery. The aim of this article is to provide proof of concept for two stage cytoreductive surgery (CRS) in this category of patients.
A two stage CRS and HIPEC with oxaliplatin was proposed for patients with bulky PMP including important involvement of the serosal surfaces of the bowel or colon who had an impaired nutritional status. The residual disease at the end of the first stage was less than 5 mm of thickness on several implants. Clinical, surgical and histopathological variables were analyzed.
All eight patients completed the two-stage strategy. Mortality was nil. One Clavien Dindo grade 3 event occurred in each stage. After a median follow up of 29.5 months, all patients were alive and free of recurrence. All of the patients had histopathological complete response on the specimens obtained from the residual sites during the second stage surgery.
Two-stage surgical strategy is feasible for bulky PMP patients and it is associated with little high-grade morbidity and enhanced visceral sparing.
Immune checkpoint inhibitors (ICI) targeting Programmed death-1 (PD-1) have shown their efficacy in advanced MSI/dMMR (microsatellite instability/deficient mismatch repair) tumors. The MSI/dMMR ...status predicts clinical response to ICI. The promising results evaluating ICI in localized MSI/dMMR tumors in neoadjuvant setting need to be confirmed in MSI/dMMR solid tumors. The aim of the IMHOTEP trial is to assess the efficacy of neoadjuvant anti-PD-1 treatment in MSI/dMMR tumors regarding the pathological complete response rate.
This study is a prospective, multicenter, phase II study including 120 patients with localized MSI/dMMR carcinomas suitable for curative surgery. A single dose of pembrolizumab will be administered before the surgery planned 6 weeks later. Primary objective is to evaluate the efficacy of neoadjuvant pembrolizumab according to pathological complete tumor response. Secondary objectives are to assess safety, recurrence-free survival and overall survival. Ancillary studies will assess molecular and immunological biomarkers predicting response/resistance to ICI. First patient was enrolled in December 2021.
The IMHOTEP trial will be one of the first clinical trial investigating perioperative ICI in localized MSI/dMMR in a tumor agnostic setting. Assessing neoadjuvant anti-PD-1 is mandatory to improve MSI/dMMR patient's outcomes. The translational program will explore potential biomarker to improve our understanding of immune escape and response in this ICI neoadjuvant setting.
The detection of a ROS1 rearrangement in advanced and metastatic lung adenocarcinoma (LUAD) led to a targeted treatment with tyrosine kinase inhibitors with favorable progression-free survival and ...overall survival of the patients. Thus, it is mandatory to screen for the ROS1 rearrangement in all these patients. ROS1 rearrangements can be detected using break-apart fluorescence in situ hybridization (FISH), which is the gold standard; however, ROS1 immunohistochemistry (IHC) can be used as a screening test because it is widely available, easy and rapid to perform, and cost-effective.
We evaluated the diagnostic accuracy and interpathologist agreement of two anti-ROS1 IHC clones, SP384 (Ventana, Tucson, Arizona) and D4D6 (Cell Signaling, Danvers, Massachusetts), in a training cohort of 51 positive ROS1 FISH LUAD cases, and then in a large validation cohort of 714 consecutive cases of LUAD from six routine molecular pathology platforms.
In the two cohorts, the SP384 and D4D6 clones show variable sensitivity and specificity rates on the basis of two cutoff points greater than or equal to 1+ (all % tumor cells) and greater than or equal to 2+ (>30% stained tumor cells). In the validation cohort, the D4D6 yielded the best accuracy for the presence of a ROS1 rearrangement by FISH. Interpathologist agreement was moderate to good (interclass correlation 0.722–0.874) for the D4D6 clone and good to excellent (interclass correlation: 0.830–0.956) for the SP384 clone.
ROS1 IHC is an effective screening tool for the presence of ROS1 rearrangements. However, users must be acutely aware of the variable diagnostic performance of different anti-ROS1 antibodies before implementation into routine clinical practice.
Pressurized intraperitoneal aerosol chemotherapy (PIPAC)–directed therapy is a new treatment option for peritoneal metastasis (PM). The 4-tiered Peritoneal Regression Grading Score (PRGS) has been ...proposed for assessment of histological treatment response. We aimed to evaluate the effect of immunohistochemistry (IHC) on interobserver agreement of the PRGS. Hematoxylin and eosin (H&E)–stained and IHC-stained slides (n = 662) from 331 peritoneal quadrant biopsies (QBs) taken prior to 99 PIPAC procedures performed on 33 patients were digitalized and uploaded to a web library. Eight raters (five consultants and three residents) assessed the PRGS, and Krippendorff's alpha coefficients (α) were calculated. Results (IHC-PRGS) were compared with data published in 2019, using H&E-stained slides only (H&E-PRGS). Overall, agreement for IHC-PRGS was substantial to almost perfect. Agreement (all raters) regarding single QBs after treatment was substantial for IHC-PRGS (α = 0.69, 95% confidence interval CI = 0.66–0.72) and moderate for H&E-PRGS (α = 0.60, 95% CI = 0.56–0.64). Agreement (all raters) regarding the mean PRGS per QB set after treatment was higher for IHC-PRGS (α = 0.78, 95% CI = 0.73–0.83) than for H&E-PRGS (α = 0.71, 95% CI = 0.64–0.78). Among residents, agreement was almost perfect for IHC-PRGS and substantial for H&E-PRGS. Agreement (all raters) regarding maximum PRGS per QB set after treatment was substantial for IHC-PRGS (α = 0.61, 95% CI = 0.54–0.68) and moderate for H&E-PRGS (α = 0.60, 95% CI = 0.53–0.66). Among residents, agreement was substantial for IHC-PRGS (α = 0.66, 95% CI = 0.57–0.75) and moderate for H&E-PRGS (α = 0.55, 95% CI = 0.45–0.64). Additional IHC seems to improve the interobserver agreement of PRGS, particularly between less experienced raters.
•Peritoneal metastasis (PM) of different origin is difficult to treat by systemic chemotherapy.•Pressurized intraperitoneal aerosol chemotherapy is a new option for PM.•The Peritoneal Regression Grading Score (PRGS) was proposed for histological response assessment.•Effect of immunohistochemistry (IHC) on interobserver agreement of the PRGS was studied.•IHC improves interobserver agreement of the PRGS, notably between less experienced raters.
In patients with advanced colorectal cancer, leucovorin, fluorouracil, and irinotecan (FOLFIRI) is considered as one of the reference first-line treatments. However, only about half of treated ...patients respond to this regimen, and there is no clinically useful marker that predicts response. A major clinical challenge is to identify the subset of patients who could benefit from this chemotherapy. We aimed to identify a gene expression profile in primary colon cancer tissue that could predict chemotherapy response.
Tumor colon samples from 21 patients with advanced colorectal cancer were analyzed for gene expression profiling using Human Genome GeneChip arrays U133. At the end of the first-line treatment, the best observed response, according to WHO criteria, was used to define the responders and nonresponders. Discriminatory genes were first selected by the significance analysis of microarrays algorithm and the area under the receiver operating characteristic curve. A predictor classifier was then constructed using support vector machines. Finally, leave-one-out cross validation was used to estimate the performance and the accuracy of the output class prediction rule.
We determined a set of 14 predictor genes of response to FOLFIRI. Nine of nine responders (100% specificity) and 11 of 12 nonresponders (92% sensitivity) were classified correctly, for an overall accuracy of 95%.
After validation in an independent cohort of patients, our gene signature could be used as a decision tool to assist oncologists in selecting colorectal cancer patients who could benefit from FOLFIRI chemotherapy, both in the adjuvant and the first-line metastatic setting.
This document is a summary of the French Intergroup guidelines regarding the management of appendicular epithelial tumors (AT) and pseudomyxoma peritonei (PMP) published in March 2020, available on ...the website of the French Society of Gastroenterology (SNFGE) (www.tncd.org).
All French medical societies specialized in the management of AT and PMP collaboratively established these recommendations based on literature until December 2019 and the results of a Delphi vote carried out by the Peritoneal Surface Oncology Group International experts, and graded into 4 categories (A, B, C, Expert Agreement) according to their level of evidence.
AT and PMP are rare but represent a wide range of clinico-pathological entities with several pathological classification systems and different biological behaviors. Their treatment modalities may vary accordingly and range from simple surveillance or laparoscopic appendectomy to complete cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) and / or systemic chemotherapy. The prognosis of these neoplasms may also largely vary according to their pathological grade and spreading at diagnosis or during the follow-up. Given the rarity of certain situations, the therapeutic strategy adapted to each patient, must be discussed in a specialized multidisciplinary meeting after a specialized pathological and radiological pre-therapeutic assessment and a clinical examination by a surgeon specializing in the management of rare peritoneal malignancies.
These recommendations are proposed to achieve the most beneficial strategy in a daily practice as the wide range and the rareness of these entities renders their management challenging. These guidelines are permanently being reviewed.
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