The assessment of tumor-infiltrating lymphocytes in invasive apocrine carcinoma of the breast in relation to the HER2 status.

In the current study, we assessed the prevalence and molecular features of HER2-low phenotype in the apocrine carcinomas of the breast (ApoCa) and its relationship with tumor-infiltrating lymphocytes (TILs). A cohort of 64 well-characterized therapy-naïve ApoCa was used. The TIL distribution was assessed using the hematoxylin and eosin whole slide/scanned images following the international TILs working group recommendations. Next-generation sequencing (NGS) was performed in a subset of HER2-low ApoCa. All patients were women, with a mean age of 62 years. Forty-three carcinomas were pure apocrine carcinoma (PAC; ER-/AR+), and the remaining 21 were classified as apocrine-like carcinomas (ALCs; ER+/-, AR+/-). HER2/neu was positive (score 3+ by IHC and/or amplified by FISH) in 20/43 (47%) PAC and 4/21 (19%) ALC. The prevalence of HER2-low expression (scores 1+ or 2+ without HER2 amplification) in ApoCa was 39% without significant differences between PAC and ALC (P = 0.14); however, the HER2-low phenotype was more prevalent in triple-negative PAC than in ALC (P < 0.001). Levels of TILs were low (≤10%) in 74% of ApoCa (median 5%, range 0%-50%). TIL levels were significantly higher in ALC than in PAC (P = 0.02). HER2 status had no impact on TIL distribution (P = 0.45). The genomic profile of HER2-low ApoCa was similar to other subtypes of ApoCa. ApoCa has predominantly low TIL, particularly PAC. The prevalence of the HER2-low phenotype in ApoCa is high, which should have therapeutic and clinical implications given the recently approved therapies with antibody-drug conjugates (ADCs) for HER2-low breast cancers.

Dietary Supplementation Before, During and After Pregnancy: Results of the Cluster-Randomized GeliS Study.

Introduction The nutritional status of women before, during, and after pregnancy plays an important role in the health of mother and child. In addition to a balanced mixed diet, the increased need for folic acid and iodine should be met and ensured with supplements. The aim of this study was to assess dietary supplementation in the context of pregnancy and to investigate the effect of targeted counselling on supplementation behavior during and after pregnancy. Methods In the context of the "Gesund leben in der Schwangerschaft" (GeliS; "Healthy living in pregnancy") trial, women in the intervention group (IG) received four structured lifestyle counselling sessions during pregnancy as well as postpartum, during which they were informed about appropriate dietary supplementation. The women in the control group (CG) received routine prenatal care. The intake of dietary supplements was recorded at different points using a questionnaire. Results In total, 2099 women were included in the analysis. Prior to conception, 31.3% of the women in the IG and 31.4% of the women in the CG took folic acid supplements. Prenatally, about half of the women took folic acid (IG: 54.1%; CG: 52.0%) and iodine (IG: 50.2%; CG: 48.2%). Statistically significant differences between the groups with regard to supplementation behavior could not be observed, neither prior to inclusion in the study nor during the intervention. During pregnancy, 23.0% of all women took docosahexaenoic acid (DHA) supplements and 21.8% iron supplements. 49.4% of the women additionally took vitamin D supplements. A higher educational level (p < 0.001), advanced age (p < 0.001), primiparity (p < 0.001), and a vegetarian diet (p = 0.037) were all associated with a higher level of dietary supplementation. Conclusion The GeliS lifestyle counselling did not significantly improve the supplementation behavior of women during and after pregnancy. Women should be informed about adequate dietary supplementation early on within the scope of gynecological prenatal care.

Composition of the immune microenvironment differs between carcinomas metastatic to the lungs and primary lung carcinomas.

Lungs are among the most common sites for development of both primary and metastatic carcinomas. Tumor cells expression (TC) of PD-L1 is an important predictor of the of response to immune check-point inhibition in NSCLC, while the composition of the immune cells (IC) in the tumor microenvironment including PD-L1+ cells is believed to predict responses in tumors of some other primary sites. Total mutational load (TML) and microsatellite instability (MSI) also play a role in response to the immune checkpoint blockade. We investigated immune microenvironment characteristics (PD-1, PD-L1, CD8) of 257 lung biopsies including 81 primary (NSCLC) and 176 metastatic tumors to the lungs. TML and MSI were calculated from massively parallel sequencing (592-gene panel). TC expression of PD-L1 was more common in NSCLC than in metastatic carcinomas (28% vs. 10%, p=0.009), while PD-L1-positive IC were present at relevant percentages (1-5%) exclusively in metastatic carcinomas (31% IC positive vs. 0%, p<0.001). Metastatic carcinomas carried significantly lower TML in comparison with the NSCLCs (6.6 mutations on average vs. 10, p=0.01). All primary NSCLC were microsatellite stable, and only 2 metastatic carcinomas exhibited MSI-H status. The number of PD-1+ and CD8+ tumor infiltrating lymphocytes did not differ significantly between the primary and metastatic carcinomas. Our study revealed significant differences in tumor immune microenvironment (PD-L1 in IC and TC), and its relationship to TML between NSCLC and metastatic cancers. These differences could determine the choice of a predictive biomarker test and subsequently effect(s) of the immune therapy treatments in various advanced cancers.

Programmed cell death 1 (PD-1) and its ligand (PD-L1) in common cancers and their correlation with molecular cancer type.

Cancer cells expressing PD-1 ligands (PD-L1/PD-L2) inhibit immune-modulatory T-cell activation facilitating disease progression. Preliminary clinical trials exploring interruption of PD-1/PD-L1 signaling showed benefit in several cancer types. We analyzed the distribution of PD-1-positive tumor-infiltrating lymphocytes (TIL) and cancer cells' expression of PD-L1 in a molecularly profiled cohort of 437 malignancies (380 carcinomas, 33 sarcomas, and 24 melanomas). We showed that the presence of PD-1(+) TILs significantly varied among cancer types (from 0% in extraskeletal myxoid chondrosarcomas to 93% in ovarian cancer), and was generally associated with the increased number of mutations in tumor cells (P = 0.029). Cancer cell expression of PD-L1 varied from absent (in Merkel cell carcinomas) to 100% (in chondro- and liposarcomas), but showed the inverse association with the number of detected mutations (P = 0.004). Both PD-1 and PD-L1 expression were significantly higher in triple-negative breast cancers (TNBC) than in non-TNBC (P < 0.001 and 0.017, respectively). Similarly, MSI-H colon cancers had higher PD-1 and PD-L1 expression than the microsatellite stable tumors (P = 0.002 and 0.02, respectively). TP53-mutated breast cancers had significantly higher PD-1 positivity than those harboring other driver mutations (e.g., PIK3CA; P = 0.002). In non-small cell lung cancer, PD-1/PD-L1 coexpression was identified in 8 cases (19%), which lacked any other targetable alterations (e.g., EGFR, ALK, or ROS1). Our study demonstrated the utility of exploring the expression of two potentially targetable immune checkpoint proteins (PD-1/PD-L1) in a substantial proportion of solid tumors, including some aggressive subtypes that lack other targeted treatment modalities.