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Background: Dose-dense sequential (dds) chemotherapy has changed the clinical outcome of patients with early breast cancer (BC). To investigate the impact of dose intensity (DI) in the adjuvant setting of BC, this observational trial (HE 10/10) was conducted assessing the long-term survival outcome, safety and toxicity of a currently widely used chemotherapeutic regimen. In addition, the prognostic significance of tumor infiltrating lymphocytes (TILs) and infiltrating CD8 + lymphocytes were also evaluated in the same cohort., Patients and Methods: Totally, 1054 patients were prospectively enrolled in the current study with 1024 patients being eligible, while adequate tissue was available for 596 of them. TILs, CD8 + lymphocytes in intratumoral areas in contact with malignant cells (iCD8), CD8 + lymphocytes in tumor stroma (sCD8) as well as the total number of CD8 + lymphocytes within the tumor area (total CD8) were assessed by immunohistochemistry., Results: Within a median follow-up of 125.18 months, a total of 200 disease-free survival (DFS) events (19.5%) were reported. Importantly, the 10-year DFS and OS rates were 78.4% (95% CI 75.0-81.5) and 81.7% (95% CI 79.0-84.1), respectively. Interestingly, higher CD8 + T cells as well as TILs in the tumor microenvironment were associated with an improved long-term survival outcome., Conclusions: In conclusion, this study confirms the significance of dds adjuvant chemotherapeutic regimen in terms of long-term survival outcome, safety and toxicity as well as the prognostic significance of TILs and infiltrating CD8 + lymphocytes in BC patients with early-stage disease., Competing Interests: Declaration of competing interest GA: Advisory Boards: Novartis, BMS, Roche Hellas, Astra Zeneca, Sanofi, Amgen, Genesis Pharma, Merck, Pfizer. DP: Advisory Role: Roche, MSD, Astellas. Honoraria: Roche, MSD, Astellas. AK: Speaker fees: Roche, MSD, Pfizer. Educational grant: Pfizer. Advisory Boards: ENETS. Adverse Events Monitoring: EOF. GR: Research funding: Tesaro, IQvia, ICON Clinical Research, MSD, PPD Global. Consulting fees: Roche, Pfizer, IQvia. Honoraria: Ipsen, MSD, Myriad. Travel: Pfizer, Merck, Sanofi, Astellas Pharma, MSD Oncology, Servier, AstraZeneca, ICON Clinical Research. FZ: Honoraria for lectures and have served in an advisory role for AstraZeneca, Daiichi, Eli- Lilly, Merck, Novartis, MSD, Pfizer, Genesis- Pharma, Roche and Gilead. GF: Advisory Board: Pfizer, Novartis. Honoraria: AstraZeneca, Novartis. Stock ownership: Genprex, Daiichi Sankyo, RFL Holdings, Formycon., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: We examined tumor genotype characteristics of human epidermal growth factor receptor 2 (HER2)-positive relapsed (R-) and de novo (dn-) metastatic breast cancer (MBC) in trastuzumab-treated patients who were previously not exposed to this agent., Materials and Methods: We analyzed genotypes obtained upon deep sequencing from 113 HER2-positive primary tumors from 69 patients with R-MBC and 44 patients with dn-MBC., Results: Mutations were observed in 90 (79.6%) tumors, 56 R-MBC and 34 dn-MBC (median number per tumor: 2; mean: 11.2; range: 0-150). The top mutated gene was TP53 (63.7%) followed by PIK3CA (24.8%) and others that were mostly co-mutated with TP53 (eg, 22 of 28 PIK3CA mutated tumors were co-mutated in TP53, 17 of these were R-MBC [P = .041]). dn-MBC had higher CEN17 average copies (P = .048). Tumor mutational burden inversely correlated with average HER2 copies (rho -0.32; P < .001). In all patients, PIK3CA mutations and higher proliferation rate were independent unfavorable prognosticators. In R-MBC, longer disease-free interval between initial diagnosis and relapse conferred lower risk for time-to-progression (P < .001) and death (P = .009); PIK3CA mutations conferred higher risk for death (P = .035). In dn-MBC, surgical removal of the primary tumor before any other therapy was favorable for time-to-progression (P = .002); higher tumor mutational burden was unfavorable for survival (P = .026)., Conclusions: Except for the overall unfavorable prognostic effect of PIK3CA mutations in trastuzumab-treated MBC, our exploratory findings indicate that the outcome of patients with R-MBC is related to patient benefit from the preceding adjuvant chemotherapy and provide initial evidence that tumor mutational burden may be related to prognosis in dn-MBC, which is of potential clinical relevance and merits further investigation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The clinical relevance of mismatch repair (MMR) status in patients with nonmetastatic cancer across tumour types remains unclear. Our goal was to investigate the prognostic role of MMR deficiency in patients with stage I-III colorectal and endometrial cancer., Methods: Patients with nonmetastatic colorectal and endometrial cancer with tumour tissue available for analysis were identified through the Hellenic Cooperative Oncology Group (HeCOG)'s tumour repository. Patients had been referred to Departments of Medical Oncology affiliated with HeCOG. MMR protein expression was evaluated by immunohistochemistry. The primary outcome measure was overall survival (OS)., Results: From May 1990 to September 2012, 1158 patients with nonmetastatic colorectal (N = 991) and endometrial cancer (N = 167) were identified (median age: 64 years, men: 544). All patients with colorectal and 109 (65%) with endometrial cancer had received adjuvant treatment. MMR deficiency was observed in 114 (11.5%) of colorectal and 80 (47.9%) of endometrial tumours. More commonly deficient proteins were PMS2 (69 patients, 7%) and MLH1 (63 patients, 6.5%) in colorectal cancer and MSH2 (58 patients, 34.7%) in endometrial cancer. Colorectal MMR-deficient (dMMR) tumours were more likely to be right sided (65 % dMMR vs 27 % proficient MMR, pMMR; p < 0.001), high grade (31% vs 15%, χ 2 , p < 0.001) and with a mucinous component (64% vs 42%, p < 0.001). Endometrial dMMR tumours were more often of endometrioid histology (51.4 % endometrioid vs 20 % serous/clear cell, p = 0.020). Compared with MMR proficiency, MMR deficiency was associated with improved OS in patients with endometrial cancer (HR = 0.38, 95% CI 0.20 to 0.76, p = 0.006), but not in patients with colorectal cancer (HR = 0.73, 95% CI 0.49 to 1.09, p = 0.130). After adjusting for age, stage and grade, MMR deficiency maintained its favourable prognostic significance in patients with endometrial cancer (HR = 0.42, 95% CI 0.20 to 0.88, p = 0.021)., Conclusions: DMMR was associated with improved outcomes in patients with nonmetastatic endometrial cancer, but not in patients with nonmetastatic colorectal cancer who received adjuvant chemotherapy., Competing Interests: Competing interests: None declared.

Background: The prognostic/predictive value of aberrant MYC gene copies and protein expression is not clear in breast cancer., Patients and Methods: Early breast cancer patients were treated with anthracycline-containing chemotherapy within 2 randomized adjuvant trials. MYC gene and centromere-8 status, as well as Myc protein expression were investigated on 1060 paraffin tumors with fluorescence in situ hybridization and immunohistochemistry, respectively., Results: MYC amplification was present in 45% and polysomy-8 in 23% of the tumors. Cytoplasmic staining was observed in 60% and nuclear staining in 26% of the tumors, strongly correlating with each other but not with MYC gene status. MYC gene amplification in the absence of polysomy-8 was associated with adverse disease-free survival (DFS) and overall survival (OS), and remained as an independent unfavorable prognostic factor in multivariate analysis (Wald P = .022 for DFS; P = .032 for OS), whereas patients with MYC amplification and polysomy-8, with polysomy-8 only, and with normal MYC without polysomy-8 performed significantly better compared with those with MYC gene amplification only. Nuclear Myc protein expression benefitted patients treated with paclitaxel (interaction P = .052 for DFS; P = .049 for OS). This interaction remained independently significant in multivariate analysis for OS (overall P = .028)., Conclusion: The effect of MYC gene status on breast cancer patient outcome seems to depend on the underlying chromosomal instability and appears unfavorable for tumors with MYC amplification without polysomy. Nuclear Myc protein expression seems predictive for benefit from adjuvant paclitaxel. These data might aid in the interpretation of relevant findings from large clinical trials., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The Androgen Receptor (AR) is a potential prognostic marker and therapeutic target in breast cancer. We evaluated AR protein expression in high-risk breast cancer treated in the adjuvant setting. Tumors were subtyped into luminal (ER+/PgR±/AR±), molecular apocrine (MAC, [ER-/PgR-/AR+]) and hormone receptor negative carcinomas (HR-negative, [ER-/PgR-/AR-]). Subtyping was evaluated with respect to prognosis and to taxane therapy. High histologic grade (p < 0.001) and increased proliferation (p = 0.001) more often appeared in MAC and HR-negative than in luminal tumors. Patients with MAC had outcome comparable to the luminal group, while patients with HR-negative disease had increased risk for relapse and death. MAC outcome was favorable upon taxane-containing treatment; this remained significant upon multivariate analysis for overall survival (HR 0.31, 95%CI 0.13-0.74, interaction p = 0.035) and as a trend for time to relapse (p = 0.15). In conclusion, AR-related subtyping of breast cancer may be prognostic and serve for selecting optimal treatment combinations., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objectives: We sought to determine the prognostic significance of the Wnt signaling pathway in operable squamous cell carcinoma of the larynx., Materials and Methods: In an annotated cohort of 289 operable laryngeal cancers we evaluated the prognostic impact of E-cadherin, P-cadherin and β-catenin protein expression with immunohistochemistry, as well as the mRNA expression of 7 key effectors of the Wnt pathway including secreted frizzled-related protein 4 (SFRP4), SNAI2 (SLUG) and WNT5A with qPCR (relative quantification [RQ])., Results: Using median immunoreactive scores as a pre-defined cut-off, patients whose tumors overexpressed both cytoplasmic E-cadherin and β-catenin experienced longer median OS as compared to those whose tumors overexpressed β-catenin only (median OS 124 vs. 72 months, p=0.0301) and patients whose tumors overexpressed both cytoplasmic and membranous E-cadherin experienced longer DFS as compared to those whose tumors overexpressed cytoplasmic E-cadherin only (median 118 vs. 91 months, p=0.0106). Upon hierarchical clustering of SFRP4, SNAI2 and WNT5A RQ values, profiles including co-expression of all 3 genes but also profiles with under-expression of SNAI2 and WNT5A were associated with worse outcome as compared to profiles not related to the Wnt pathway. In multivariate analysis, clustering was an independent predictor for DFS (p=0.0221) and OS (p=0.0077)., Conclusion: We identified gene expression profiles and IHC patterns associated with aberrant Wnt signaling conferring aggressive clinical behavior in operable squamous cell carcinoma of the larynx. Prospective validation of these results will determine whether targeting the Wnt pathway merits investigation in this disease., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Hypothesising that cancer of unknown primary (CUP) may harbour unique characteristics, we present a translational study of the immunohistochemical expression and clinical correlation of key PTEN/AKT pathway molecules., Patients and Methods: We collected 100 paraffin-embedded CUP tissue blocks. We studied using tissue microarrays the expression of PTEN, phospho-AKT, Cyclin D1, p21, phospho-RPS6. From the percentage of staining tumour cells and the literature, we selected cut-offs to classify the expression of each biomolecule. We correlated IHC expression with clinical data., Results: PTEN, pAKT, and pRPS6 showed frequent expression. At univariate analysis, high IHC expression of pAKT and pRPS6 displayed statistically significant association with worse survival. Prognosis was worse upon concurrent high IHC expression of pMAPK and pAKT {median overall survival = 8 months [95% confidence interval (CI) 5.3-10.7] versus 17 months [95% CI 13.1-20.9]}. In multivariate analysis, high p21 was associated with better survival (risk ratio [RR] = 0.34 [95% CI 0.16-0.73], P = 0.005). High expression of pAKT (RR = 2.39 [95% CI 1.23-4.66], P = 0.01) or pRPS6 (RR = 2.76 [95% CI 1.31-5.84], P = 0.008) was associated with worse survival., Conclusions: p21 expression conferred favourable prognosis, while high pAKT or pRPS6 expression predicted worse prognosis. Concurrent MAPK and pAKT expression had a marked adverse impact on survival.

Background: Despite improvement in therapeutic techniques, patients with early-stage laryngeal cancer still recur after treatment. Gene expression prognostic models could suggest which of these patients would be more appropriate for testing adjuvant strategies., Materials and Methods: Expression profiling using whole-genome DASL arrays was carried out on 56 formalin-fixed paraffin-embedded tumor samples of patients with early-stage laryngeal cancer. We split the samples into a training and a validation set. Using the supervised principal components survival analysis in the first cohort, we identified gene expression profiles that predict the risk of recurrence. These profiles were then validated in an independent cohort., Results: Gene models comprising different number of genes identified a subgroup of patients who were at high risk of recurrence. Of these, the best prognostic model distinguished between a high- and a low-risk group (log-rank P<0.005). The prognostic value of this model was reproduced in the validation cohort (median disease-free survival: 38 versus 161 months, log-rank P=0.018), hazard ratio=5.19 (95% confidence interval 1.14-23.57, P<0.05)., Conclusions: We have identified gene expression prognostic models that can refine the estimation of a patient's risk of recurrence. These findings, if further validated, should aid in patient stratification for testing adjuvant treatment strategies.

Background: Concomitant administration of radiation therapy (RT) and chemotherapy with cisplatin (CCRT) is considered standard treatment in patients with locally advanced nasopharyngeal cancer (LA-NPC). The role of induction chemotherapy (IC) when followed by CCRT in improving locoregional control remains controversial., Patients and Methods: Totally, 141 eligible patients with LA-NPC were randomized to either three cycles of IC with cisplatin 75 mg/m(2), epirubicin 75 mg/m(2) and paclitaxel (Taxol) 175 mg/m(2) (CEP) every 3 weeks followed by definitive RT (70 Gy) and concomitant weekly infusion of cisplatin 40 mg/m(2) (investigational arm, 72 patients) or to the same CCRT regimen alone (control arm, 69 patients)., Results: Sixty-two patients (86%) received three cycles of IC. No difference between the arms was observed in the number of patients who completed RT (61 versus 64, P = 018). Overall and complete response rates were very similar in the two arms and so were 3-year progression-free and overall survival rates. Grade III or IV toxic effects from IC were infrequent, apart of alopecia. Mucositis, weight loss and leukopenia were the most prominent side-effects from CCRT., Conclusion: IC with three cycles of CEP when followed by CCRT did not significantly improve response rates and/or survival compared with that of CCRT alone.

Purpose: This phase II study sought to evaluate the efficacy of the paclitaxel-carboplatin combination as neoadjuvant chemotherapy in patients with locally advanced breast cancer (LABC)., Patients and Methods: A total of 46 patients with LABC and inflammatory breast cancer (IBC) received 6 cycles of paclitaxel 175 mg/m2, followed by carboplatin, at an area under the curve of 6, before mastectomy. The primary endpoint constituted response to chemotherapy. We studied ERCC1 protein, microtubule-associated protein-tau, estrogen receptor, progesterone receptor, epidermal growth factor receptor (EGFR), HER2, and Ki-67 immunohistochemically in tissue microarray and whole-tissue sections. In addition, EGFR and HER2 gene status was assessed by fluorescence in situ hybridization. Predictive and prognostic molecular markers were retrospectively investigated., Results: A total of 42 female patients were considered eligible. Forty percent had IBC. Twenty-five patients (60%) experienced a clinical response, and 4 patients (9.5%) experienced a pathologic complete response. Chemotherapy was well tolerated. After a median follow-up of 45 months (range, 8.8-64.8 months), the estimated 3-year progression-free survival (PFS) was 54%, and the 3-year overall survival (OS) was 66%. The overexpression of EGFR protein was associated with a lower response rate (0 vs. 67%; P = .023), whereas high Ki-67 expression, high-grade tumors, tumor stage T4, and triple-negative tumors were associated with poorer PFS. Only high-grade tumors were associated with a significantly shorter OS (P = .004)., Conclusion: The combination of paclitaxel and carboplatin is an effective and well-tolerated regimen in female patients with LABC.

HER2-positive breast cancer is characterized by aggressive growth and poor prognosis. Women with metastatic breast cancer with over-expression of HER2 protein or excessive presence of HER2 gene copies are potential candidates for Herceptin (Trastuzumab) targeted treatment that binds to HER2 receptors on tumor cells and inhibits tumor cell growth. Fluorescence in situ hybridization (FISH) is one of the most widely used methods to determine HER2 status. Typically, evaluation of FISH images involves manual counting of FISH signals in multiple images, a time consuming and error prone procedure. Recently, we developed novel software for the automated evaluation of FISH images and, in this study, we present the first testing of this software on images from two separate research clinics. To our knowledge, this is the first concurrent evaluation of any FISH image analysis software in two different clinics. The evaluation shows that the developed FISH image analysis software can accelerate evaluation of HER2 status in most breast cancer cases.