PURPOSE Preclinical data suggest a contribution of the immune system to chemotherapy response. In this study, we investigated the prespecified hypothesis that the presence of a lymphocytic infiltrate in cancer tissue predicts the response to neoadjuvant chemotherapy. METHODS We investigated intratumoral and stromal lymphocytes in a total of 1,058 pretherapeutic breast cancer core biopsies from two neoadjuvant anthracycline/taxane-based studies (GeparDuo, n = 218, training cohort; and GeparTrio, n = 840, validation cohort). Molecular parameters of lymphocyte recruitment and activation were evaluated by kinetic polymerase chain reaction in 134 formalin-fixed, paraffin-embedded tumor samples. Results In a multivariate regression analysis including all known predictive clinicopathologic factors, the percentage of intratumoral lymphocytes was a significant independent parameter for pathologic complete response (pCR) in both cohorts (training cohort: P = .012; validation cohort: P = .001). Lymphocyte-predominant breast cancer responded, with pCR rates of 42% (training cohort) and 40% (validation cohort). In contrast, those tumors without any infiltrating lymphocytes had pCR rates of 3% (training cohort) and 7% (validation cohort). The expression of inflammatory marker genes and proteins was linked to the histopathologic infiltrate, and logistic regression showed a significant association of the T-cell-related markers CD3D and CXCL9 with pCR. CONCLUSION The presence of tumor-associated lymphocytes in breast cancer is a new independent predictor of response to anthracycline/taxane neoadjuvant chemotherapy and provides useful information for oncologists to identify a subgroup of patients with a high benefit from this type of chemotherapy.

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The classification of neuroendocrine neoplasms (NENs) differs between organ systems and currently causes considerable confusion. A uniform classification framework for NENs at any anatomical location may reduce inconsistencies and contradictions among the various systems currently in use. The classification suggested here is intended to allow pathologists and clinicians to manage their patients with NENs consistently, while acknowledging organ-specific differences in classification criteria, tumor biology, and prognostic factors. The classification suggested is based on a consensus conference held at the International Agency for Research on Cancer (IARC) in November 2017 and subsequent discussion with additional experts. The key feature of the new classification is a distinction between differentiated neuroendocrine tumors (NETs), also designated carcinoid tumors in some systems, and poorly differentiated NECs, as they both share common expression of neuroendocrine markers. This dichotomous morphological subdivision into NETs and NECs is supported by genetic evidence at specific anatomic sites as well as clinical, epidemiologic, histologic, and prognostic differences. In many organ systems, NETs are graded as G1, G2, or G3 based on mitotic count and/or Ki-67 labeling index, and/or the presence of necrosis; NECs are considered high grade by definition. We believe this conceptual approach can form the basis for the next generation of NEN classifications and will allow more consistent taxonomy to understand how neoplasms from different organ systems inter-relate clinically and genetically.

Immunologic factors were highly significant predictors of therapy response in the GeparSixto trial, particularly in patients treated with Cb. After further standardization, they could be included in histopathologic assessment of BC.

Breast cancers are either primarily resistant to chemotherapy (intrinsic resistance), or respond to chemotherapy but later recur with a multidrug-resistant phenotype because of overexpression of the multidrug transporter P-glycoprotein. The MDR1 gene encoding P-glycoprotein may be transcriptionally regulated by a Y-box transcription factor. We now report that, in multidrug-resistant MCF-7 breast cancer cells, nuclear localization of YB-1 is associated with MDR-1 gene expression. In drug-sensitive MCF-7 cells, however, YB-1 was localized to the cytoplasm. Regulated overexpression of YB-1 in drug-sensitive diploid breast epithelial cells induced MDR-1 gene expression and multidrug resistance. In 27 out of 27 untreated primary breast cancers, YB-1 protein was expressed in the cytoplasm although it was undetectable in normal breast tissue of these patients. In a subgroup of tumors (9/27), however, YB-1 was also localized to the nucleus and, in these cases, high levels of P-glycoprotein were present. These results show that in a subset of untreated primary breast cancers, nuclear localization of YB-1 protein is associated with intrinsic multidrug resistance. Our data show that YB-1 has an important role in controlling MDR1 gene transcription and this finding provides a basis for the analysis of molecular mechanisms responsible for intrinsic multidrug resistance in human breast cancer.

Trastuzumab-based therapy has been shown to confer overall survival benefit in HER2-positive patients with advanced gastric cancer in a large multicentric trial (ToGA study). Subgroup analysis identified adenocarcinomas of the stomach and gastroesophageal (GE) junction with overexpression of HER2 according to immunohistochemistry (IHC) as potential responders. Due to recent approval of trastuzumab for HER2 positive metastatic gastric and GE-junction cancer in Europe (EMEA) HER2 diagnostics is now mandatory with IHC being the primary test followed by fluorescence in situ hybridization (FISH) in IHC2+ cases. However, in order to not miss patients potentially responding to targeted therapy determination of a HER2-positive status for gastric cancer required modification of scoring as had been proposed in a pre-ToGA study. To validate this new HER2 status testing procedure in terms of inter-laboratory and inter-observer consensus for IHC scoring a series of 547 gastric cancer tissue samples on a tissue microarray (TMA) was used. In the first step, 30 representative cores were used to identify specific IHC HER2 scoring issues among eight French and German laboratories, while in the second step the full set of 547 cores was used to determine IHC HER2 intensity and area score concordance between six German pathologists. Specific issues relating to discordance were identified and recommendations formulated which proved to be effective to reliably determine HER2 status in a prospective test series of 447 diagnostic gastric cancer specimens.

Immunohistochemistry of the PD-L1 protein may be predictive for anti-PD-1 and anti-PD-L1 immunotherapy in pulmonary adenocarcinoma and in clinically unselected cohorts of so-called non-small-cell lung cancer. Several PD-L1 immunohistochemistry assays with custom reagents and scoring-criteria are developed in parallel. Biomarker testing and clinical decision making would profit from harmonized PD-L1 diagnostics. To assess interobserver concordance and PD-L1 immunohistochemistry staining patterns, 15 pulmonary carcinoma resection specimens (adenocarcinoma: n=11, squamous-cell carcinoma: n=4) were centrally stained with the assays 28-8, 22C3, SP142, and SP263 according to clinical trial protocols. The slides were evaluated independently by nine pathologists. Proportions of PD-L1-positive carcinoma cells and immune cells were scored according to a 6-step system that integrates the criteria employed by the four PD-L1 immunohistochemistry assays. Proportion scoring of PD-L1-positive carcinoma cells showed moderate interobserver concordance coefficients for the 6-step scoring system (Light's kappa=0.47-0.50). The integrated dichotomous proportion cut-offs (≥1, ≥5, ≥10, ≥50%) showed good concordance coefficients (κ=0.6-0.8). Proportion scoring of PD-L1-positive immune cells yielded low interobserver concordance coefficients both for the 6-step-score (κ<0.2) and the dichotomous cut-offs (κ=0.12-0.25). The assays 28-8 and 22C3 stained similar proportions of carcinoma cells in 12 of 15 cases. SP142 stained fewer carcinoma cells compared to 28-8, 22C3, and SP263 in four cases, whereas SP263 stained more carcinoma cells in nine cases. SP142 and SP263 stained immune cells more intensely. The data indicate that carcinoma cells can be reproducibly scored in PD-L1 immunohistochemistry for pulmonary adenocarcinoma and squamous-cell carcinoma. No differences in interobserver concordance were noticed among the tested assays. The scoring of immune cells yielded low concordance rates and might require specific standardization. The four tested PD-L1 assays did not show comparable staining patterns in all cases. Thus, studies that correlate staining patterns and response to immunotherapy are required to test the significance of the observed differences.

High activity of histone deacetylases (HDACs) causes epigenetic alterations associated with malignant cell behaviour. Consequently, HDAC inhibitors have entered late-phase clinical trials as new antineoplastic drugs. However, little is known about expression and function of specific HDAC isoforms in human tumours including prostate cancer. We investigated the expression of class I HDACs in 192 prostate carcinomas by immunohistochemistry and correlated our findings to clinicopathological parameters including follow-up data. Class I HDAC isoforms were strongly expressed in the majority of the cases (HDAC1: 69.8%, HDAC2: 74%, HDAC3: 94.8%). High rates of HDAC1 and HDAC2 expression were significantly associated with tumour dedifferentiation. Strong expression of all HDACs was accompanied by enhanced tumour cell proliferation. In addition, HDAC2 was an independent prognostic marker in our prostate cancer cohort. In conclusion, we showed that the known effects of HDACs on differentiation and proliferation of cancer cells observed in vitro can also be confirmed in vivo. The class I HDAC isoforms 1, 2 and 3 are differentially expressed in prostate cancer, which might be important for upcoming studies on HDAC inhibitors in this tumour entity. Also, the highly significant prognostic value of HDAC2 clearly deserves further study.