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The prognostic value of the immune cell infiltrate in the breast carcinoma microenvironment is still uncertain. We reviewed published articles analysing the infiltration of inflammatorycells in the microenvironment of breast carcinoma. Data revealed the importance of infiltration of these immune cells in the prognosis of breast carcinoma, particularly the triple-negative and HER2-positive phenotypes. Tumour-infiltrating lymphocytes and their subtypes play a fundamental role in predicting the pathological complete response (pCR) to neoadjuvant chemotherapy. More research aiming to dissect a complex network of communication between cancer cells and other cellular components of the tumour microenvironment is necessary to develop more effective therapeutic approaches.

The response of human epidermal growth factor receptor2 (HER2)- positive breast cancer (BC) patients to anti-HER2 targeted therapy is significant. However, the response is not uniform and a proportion of HER2-positive patients do not respond. This study aims to identify predictors of response in the neoadjuvant treatment and to assess the discordance rate of HER2 status between pre- and post-treatment specimens in HER2-positive BC patients. The study group comprised 500 BC patients treated with neoadjuvant chemotherapy (NACT) and/or neoadjuvant anti-HER2 therapy and surgery who had tumours that were 3+ or 2+ with HER2 immunohistochemistry (IHC). HER2 IHC 2+ tumours were classified into five groups by fluorescence in situ hybridisation (FISH) according to the 2018 ASCO/CAP guidelines of which Groups 1, 2 and 3 were considered HER2 amplified. Pathological complete response (pCR) was more frequent in HER2 IHC 3+ tumours than in HER2 IHC 2+/HER2 amplified tumours, when either in receipt of NACT alone (38% versus 13%; p = 0.22) or neoadjuvant anti-HER2 therapy (52% versus 20%; p < 0.001). Multivariate logistic regression analysis showed that HER2 IHC 3+ and histological grade 3 were independent predictors of pCR following neoadjuvant anti-HER2 therapy. In the HER2 IHC 2+/HER2 amplified tumours or ASCO/CAP FISH Group 1 alone, ER-negativity was an independent predictor of pCR following NACT and/or neoadjuvant anti-HER2 therapy. In the current study, 22% of HER2-positive tumours became HER2-negative by IHC and FISH following neoadjuvant treatment, the majority (74%) HER2 IHC 2+/HER2 amplified tumours. Repeat HER2 testing after neoadjuvant treatment should therefore be considered.

Extramedullary haematopoiesis (EMH) in the axillary lymph node of breast cancer patients is extremely rare but when encountered can represent a diagnostic challenge. We aim to highlight this incidental finding as a diagnostic pitfall which can be mistaken for metastatic carcinoma (particularly of the metaplastic type). We report the case of a 68-year-old Caucasian female with a family history of cancer. Core biopsy revealed that she had grade II oestrogen receptor-negative, Her2-positive invasive ductal carcinoma. She was offered neoadjuvant chemotherapy with Herceptin and subsequently underwent breast-conserving surgery. Microscopic examination of the post-treatment breast surgical specimen showed a partial pathological response with large areas of tumour regression. The sentinel lymph node showed frequent large single and multinucleate giant cells with hyperchromatic nuclei located predominantly within the subcapsular and medullary sinuses. The morphological differentials of metastatic carcinoma, sinus histiocytosis and extramedullary haematopoiesis were considered. A panel of immunohistochemistry showed these large cells to be negative for epithelial markers and CD68. They were strongly positive for CD42b (megakaryocyte marker). Smaller myeloperoxidase and factor VIII-positive cells were identified. The findings confirmed EMH. Sentinel nodes are often well scrutinised by pathologists for evidence of metastatic carcinoma as an important prognostic parameter both in the standard and neoadjuvant setting. Nodal megakaryocytes have been described in response to neoadjuvant chemotherapy particularly in association with Herceptin treatment. Pathologists’ awareness of this finding in the neoadjuvant setting is crucial to avoid a mistaken diagnosis of malignancy. A relevant immunohistochemical panel together with careful attention to morphology should help establish the correct diagnosis.

Background The ASCO/CAP guidance on HER2 testing in breast cancer (BC) has recently changed. Group 2 tumours with immunohistochemistry score 2+ and HER2 / CEP17 ratio ≥2.0 and HER2 copy number <4.0 signals/cell were re-classified as HER2 negative. This study aims to examine the response of Group 2 tumours to neoadjuvant chemotherapy (NACT). Methods 749 BC cases were identified from 11 institutions. The association between HER2 groups and pathological complete response (pCR) was assessed. Results 54% of immunohistochemistry HER2 positive (score 3+) BCs showed pCR, compared to 19% of immunohistochemistry 2+ FISH amplified cases. 27% of Group 2 treated with HER2 targeted therapy achieved pCR, compared to 19 and 11% in the combined Groups 1 + 3 and Groups 4 + 5, respectively. No difference in pCR rates was identified between Group 2 and Group 1 or combined Groups 1 + 3. However, Group 2 response rate was higher than Groups 4 + 5 ( p  = 0.017). Conclusion No difference in pCR was detected in tumours with a HER2/ CEP17 ratio ≥2.0 and a HER2 score 2+ by IHC when stratified by HER2 gene copy number. Our data suggest that ASCO/CAP HER2 Group 2 carcinomas should be evaluated further with respect to eligibility for HER2 targeted therapy.

Abstract Introduction: Inflammatory breast cancer (IBC) is an aggressive form of breast cancer with a poorly characterized immune microenvironment. Methods: We used a five-colour multiplex immunofluorescence panel, including CD68, CD4, CD8, CD20, and FOXP3 for immune microenvironment profiling in 93 treatment-naïve IBC samples. Results: Lower grade tumours were characterized by decreased CD4+ cells but increased accumulation of FOXP3+ cells. Increased CD20+ cells correlated with better response to neoadjuvant chemotherapy and increased CD4+ cells infiltration correlated with better overall survival. Pairwise analysis revealed that both ER+ and triple-negative breast cancer were characterized by co-infiltration of CD20 + cells with CD68+ and CD4+ cells, whereas co-infiltration of CD8+ and CD68+ cells was only observed in HER2+ IBC. Co-infiltration of CD20+, CD8+, CD4+, and FOXP3+ cells, and co-existence of CD68+ with FOXP3+ cells correlated with better therapeutic responses, while resistant tumours were characterized by co-accumulation of CD4+, CD8+, FOXP3+, and CD68+ cells and co-expression of CD68+ and CD20+ cells. In a Cox regression model, response to therapy was the most significant factor associated with improved patient survival. Conclusion: Those results reveal a complex unique pattern of distribution of immune cell subtypes in IBC and provide an important basis for detailed characterization of molecular pathways that govern the formation of IBC immune landscape and potential for immunotherapy.

Purpose Growing evidence suggests that immunotherapy (IM) benefits non-small cell lung cancer (NSCLC) patients without identified genetic alterations. This meta-analysis evaluates the efficacy and safety of combining IM + CH compared to chemotherapy (CH) alone or with a placebo in NSCLC patients lacking EGFR/ALK mutations and without prior systemic treatment. Method We performed a comprehensive search in databases including PubMed, Scopus, Web of Science, Clinicaltrial.gov, and Cochrane Library. Statistical analysis was done using R 4.2.2, with heterogeneity assessed via the Cochrane Q test and I² statistic. Publication bias was checked using funnel plots and Egger’s regression test, with a p-value < 0.05 indicating significant asymmetry. A random-effects model was used to account for potential variability between studies. Subgroup analyses were conducted based on PD-L1 expression levels (< 1%, 1–49%, and ≥ 50%) to evaluate differential treatment effects. All statistical tests were two-sided, and a p-value < 0.05 was considered statistically significant. Result This meta-analysis evaluates the impact of IM + CH compared to CH alone (or with placebo) on overall survival (OS) and progression-free survival (PFS) across different PD-L1 expression levels. The findings indicate a significant survival advantage for combination therapy in the total population, with pooled hazard ratios (HRs) consistently below 1. OS showed a 32–36% reduction in the risk of death (HR: 0.6789, 95% CI: 0.6160–0.7482, p  < 0.0001), while PFS demonstrated a 44% decrease in disease progression risk (HR: 0.5412, 95% CI: 0.4665–0.6280, p  < 0.0001). Subgroup analyses confirmed survival benefits across all PD-L1 expression levels, with OS improvements of 30% (PD-L1 < 1%), 39% (PD-L1 1–49%), and 38% (PD-L1 ≥ 50%). Similarly, PFS benefits were observed in all subgroups, with the greatest effect in PD-L1 ≥ 50% (HR: 0.4113, 95% CI: 0.3325–0.5087, p  < 0.0001), indicating a 59% reduction in progression risk. The risk of any grade adverse events (AEs) was comparable between IM + CH and CH alone (RR 1.0070, 95% CI: 0.9987–1.0155, p  = 0.0986), while IM + CH significantly increased the risk of severe (grade ≥ 3) AEs (RR 1.1507, 95% CI: 1.0835–1.2221, p  < 0.0001). Conclusion This meta-analysis provides strong evidence that IM combined with CH is a more effective treatment strategy than CH alone or with placebo for NSCLC patients without EGFR/ALK alterations, regardless of PD-L1 expression. The combination therapy consistently improved both OS and PFS across all patient subgroups, with greater benefits observed in those with higher PD-L1 expression. For any-grade AEs, the risk slightly increases with IM + CH, but the difference is not statistically significant. However, for grade ≥ 3 AEs, IM + CH significantly raises the risk compared to CH alone or with a placebo, highlighting the need for careful monitoring in clinical practice.

The assessment of PD-L1 expression in TNBC is a prerequisite for selecting patients for immunotherapy. The accurate assessment of PD-L1 is pivotal, but the data suggest poor reproducibility. A total of 100 core biopsies were stained using the VENTANA Roche SP142 assay, scanned and scored by 12 pathologists. Absolute agreement, consensus scoring, Cohen’s Kappa and intraclass correlation coefficient (ICC) were assessed. A second scoring round after a washout period to assess intra-observer agreement was carried out. Absolute agreement occurred in 52% and 60% of cases in the first and second round, respectively. Overall agreement was substantial (Kappa 0.654–0.655) and higher for expert pathologists, particularly on scoring TNBC (6.00 vs. 0.568 in the second round). The intra-observer agreement was substantial to almost perfect (Kappa: 0.667–0.956), regardless of PD-L1 scoring experience. The expert scorers were more concordant in evaluating staining percentage compared with the non-experienced scorers (R2 = 0.920 vs. 0.890). Discordance predominantly occurred in low-expressing cases around the 1% value. Some technical reasons contributed to the discordance. The study shows reassuringly strong inter- and intra-observer concordance among pathologists in PD-L1 scoring. A proportion of low-expressors remain challenging to assess, and these would benefit from addressing the technical issues, testing a different sample and/or referring for expert opinions.

Oestrogen receptor (ER)-positive breast cancer (BC) is generally well responsive to endocrine therapy. Neoadjuvant endocrine therapy (NAET) is increasingly being used for downstaging ER-positive tumours. This study aims to analyse the effect of NAET on a well-characterised cohort of ER-positive BC with particular emphasis on receptor expression. This is a retrospective United Kingdom (UK) multicentre study of 391 patients who received NAET between October 2012 and October 2020. Detailed analyses of the paired pre- and post-NAET morphological changes and hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) expression were performed. The median duration of NAET was 86 days, with median survival and overall survival rates of 380 days and 93.4%, respectively. A total of 90.3% of cases achieved a pathological partial response, with a significantly higher rate of response in the HER2-low cancers. Following NAET, BC displayed some pathological changes involving the tumour stroma including central scarring and an increase in tumour infiltrating lymphocytes (TILs) and tumour cell morphology. Significant changes associated with the duration of NAET were observed in tumour grade (30.6% of cases), with downgrading identified in 19.3% of tumours (p < 0.001). The conversion of ER status from positive to low or negative was insignificant. The conversion of progesterone receptor (PR) and HER2 status to negative status was observed in 31.3% and 38.1% of cases, respectively (p < 0.001). HER2-low breast cancer decreased from 63% to 37% following NAET in the paired samples. Significant morphological and biomarker changes involving PR and HER2 expression occurred following NAET. The findings support biomarker testing on pre-treatment core biopsies and post-treatment residual carcinoma.

IntroductionAndrogen receptor (AR) is one of the predominant nuclear hormone receptors in invasive breast cancer and can be explored as a biomarker of response for targeted anti-androgen therapy, especially in the setting of triple negative breast cancer (TNBC). Luminal AR is a distinct subtype amongst TNBC cases following gene expression studies. TNBC is higher in Africans (23%–82%) and African-Americans (29.8%) compared to Caucasian (10%–15%) breast cancer patients; however, there is a paucity of data on AR expression in this population. The aim of this study is to determine the expression of AR and the proportion of AR positive cancers in TNBCs at the Lagos University Teaching Hospital, Lagos, Nigeria.MethodologyOut of 99 reviewed cases, 78 formalin fixed, paraffin embedded TNBC cases were assembled into a tissue microarray, stained and analysed for AR expression using immunohistochemistry.ResultsThe mean age of the TNBC patients was 49.3 years (range: 20–80 years). The histologic types in this study were invasive carcinoma (no special type) 75.4%; metaplastic carcinoma 21.4%; lobular carcinoma and mucinous carcinoma 1.6% each. Of 61 TNBC cases analysed, 37.7% were AR positive and 62.3% were AR negative, making the latter to become quadruple negative breast cancers. There was a significant association between age and AR expression (p = 0.02). In the subjects that expressed AR positivity, patients below 50 years accounted for 34.8% (8 of 23) while 65.2% (15 of 23) were above 50 years. There was no significant association between AR expression and histologic type or tumour grade.ConclusionOver a third of this Nigerian TNBC cohort study is AR+. This warrants further exploration of the predictive and prognostic significance of its expression amongst TNBC and the potential for targeted therapy, specifically androgen antagonists to improve the outcome of this disease with limited therapeutic options.