<div>AbstractPurpose:<p>Conflicting data have been reported on the prognostic value of PD-L1 protein and gene expression in breast cancer.</p><p><b>Experimental Design:</b> Medline, Embase, Cochrane Library, and Web of Science Core Collection were searched, and data were extracted independently by two researchers. Outcomes included pooled PD-L1 protein positivity in tumor cells, immune cells, or both, per subtype and per antibody used, and its prognostic value for disease-free and overall survival. A pooled gene expression analysis of 39 publicly available transcriptomic datasets was also performed.</p>Results:<p>Of the initial 4,184 entries, 38 retrospective studies fulfilled the predefined inclusion criteria. The overall pooled PD-L1 protein positivity rate was 24% (95% CI, 15%–33%) in tumor cells and 33% (95% CI, 14%– 56%) in immune cells. PD-L1 protein expression in tumor cells was prognostic for shorter overall survival (HR, 1.63; 95% CI, 1.07–2.46; <i>P</i> = 0.02); there was significant heterogeneity (<i>I<sup>2</sup></i> = 80%, <i>P</i><sub>heterogeneity</sub> < 0.001). In addition, higher PD-L1 gene expression predicted better survival in multivariate analysis in the entire population (HR, 0.82; 95% CI, 0.74–0.90; <i>P</i> < 0.001 for OS) and in basal-like tumors (HR, 0.64; 95% CI, 0.52–0.80; <i>P</i> < 0.001 for OS; <i>P</i><sub>interaction</sub> 0.005).</p>Conclusions:<p>The largest to our knowledge meta-analysis on the subject informs on PD-L1 protein positivity rates and its prognostic value in breast cancer. Standardization is needed prior to routine implementation. PD-L1 gene expression is a promising prognostic factor, especially in basal-like breast cancer. Discrepant prognostic information might be related to PD-L1 gene expression in the stroma.</p></div>
Abstract Emerging data indicate that genomic alterations can shape immune cell composition in early breast cancer. However, there is a need for complementary imaging and sequencing methods for the quantitative assessment of combined somatic copy number alteration (SCNA) and immune profiling in pathological samples. Here, we tested the feasibility of three approaches—CUTseq, for high-throughput low-input SCNA profiling, multiplexed fluorescent immunohistochemistry (mfIHC) and digital-image analysis (DIA) for quantitative immuno-profiling- in archival formalin-fixed paraffin-embedded (FFPE) tissue samples from patients enrolled in the randomized SBG-2004-1 phase II trial. CUTseq was able to reproducibly identify amplification and deletion events with a resolution of 100 kb using only 6 ng of DNA extracted from FFPE tissue and pooling together 77 samples into the same sequencing library. In the same samples, mfIHC revealed that CD4 + T-cells and CD68 + macrophages were the most abundant immune cells and they mostly expressed PD-L1 and PD-1. Combined analysis showed that the SCNA burden was inversely associated with lymphocytic infiltration. Our results set the basis for further applications of CUTseq, mfIHC and DIA to larger cohorts of early breast cancer patients.
Background Dose‐dense (DD) adjuvant chemotherapy improves outcomes in early breast cancer (BC). However, there are no phase 3 randomized data to inform on its combination with trastuzumab for patients with human epidermal growth factor receptor 2 (HER2)–positive disease. Methods This was a protocol‐predefined secondary analysis of the randomized phase 3 Pan‐European Tailored Chemotherapy (PANTHER) trial. Women 65 years old or younger with node‐positive or high‐risk, node‐negative BC were randomized 1:1 to either tailored (according to hematologic nadirs) and DD epirubicin and cyclophosphamide followed by docetaxel or standard 5‐fluorouracil, epirubicin, and cyclophosphamide plus docetaxel every 3 weeks. Patients with HER2‐positive disease received 1 year of adjuvant trastuzumab. The primary endpoint was BC relapse–free survival. In addition, HER2‐positive patients and an equal number of HER2‐negative patients matched for age, treatment group, and institution who were enrolled at Swedish sites were asked to participate in a predefined study of cardiac safety and underwent echocardiography or multigated acquisition scanning and electrocardiography at the baseline and at 4 and 6 years of follow‐up. Results There were 342 HER2‐positive patients; 335 received at least 1 dose of trastuzumab, and 29 patients discontinued trastuzumab prematurely. Relapse‐free survival was not statistically significantly in favor of the tailored and DD group (hazard ratio, 0.68; 95% confidence interval, 0.37‐1.27; P = .231). Cardiac outcomes after 4 and 6 years of follow‐up did not differ significantly between HER2‐positive and HER2‐negative patients or between the 2 treatment groups. Conclusions The combination of DD chemotherapy and trastuzumab decreased the relative risk for relapse by 32% in comparison with standard treatment, a statistically nonsignificant difference. Its efficacy and safety merit further evaluation as part of both escalation and de‐escalation strategies.
Abstract Background The detection of circulating tumour cells (CTC) is prognostic for disease recurrence in early breast cancer (BC). This study aims to investigate whether this prognostic effect persists or varies over time. Methods The study population consisted of prospectively included stage I–III BC patients. The presence of CK19 mRNA-positive CTC in the peripheral blood was evaluated before and after adjuvant chemotherapy, using a real-time RT–PCR assay. Longitudinal samples were collected for a subset of patients. Results Baseline CTC data were available from 1220 patients, while 1132 had both pre- and post-therapy data. After a median follow-up of 134.1 months, CTC positivity at baseline was associated with shorter overall survival (OS; HR adj = 1.72, 95% CI 1.34–2.21, p < 0.001). For disease-free survival, an interaction with time ( p = 0.045) was observed. CTC positivity predicted early (within 5 years; HR adj = 1.76, 95 % CI 1.33–2.32, p < 0.001) but not late recurrence (HR adj = 1.10, 95% CI 0.79–1.53, p = 0.577). Following adjuvant chemotherapy, more patients converted from CTC-positive to CTC-negative than vice versa ( p < 0.001). Ten-year OS was 68.6% for + /+ and 86.7% for −/− group ( p < 0.001). CTC status at follow-up predicted disease recurrence. Conclusion CTC detection pre- and post-adjuvant chemotherapy is prognostic for early relapse, supporting investigations for novel adjuvant therapeutic approaches.
Primary bone lymphoma is a rare disease, representing less than 5% of all extra-nodal non-Hodgkin lymphomas.We retrospectively searched the database of the lymphoma unit, Hematology/Lymphoma Department, Athens General Hospital 'Evangelismos' for primary bone lymphoma patients. Demographic and clinicopathologic data were collected and overall survival was analyzed. A log-rank test was used in a univariate analysis to identify factors affecting overall survival.We identified 24 and analyzed data from 22 patients. 12 were male (54.5%) and 10 female (45.4%) and their median age was 55 years (range: 19-83). Most patients had localized disease at the time of diagnosis (n = 19, 86.3%), the most common site was the spine (n = 11, 50%) and the most common histology was diffuse large B-cell lymphoma. 21 patients received chemotherapy as initial therapy and 16 received combined chemoradiation. 81.8% of the patients (n = 18) achieved complete remission. 5-year survival rate was 86.3% and overall survival was found to be affected by the patients' initial response to treatment.Primary bone lymphoma is usually associated with a good prognosis. Prospective studies are needed in order to clarify the effect of immunochemotherapy in overall survival.
Background: Hormone receptor expression is a known positive prognostic and predictive factor in breast cancer. However, limited evidence exists on the impact of hormone receptor status on clinical behavior and outcomes in young patients harboring BRCA pathogenic variant (PV). Methods: This is an international, multicenter, hospital-based, retrospective cohort study including young patients (≤40 years) diagnosed with invasive breast cancer between January 2000 and December 2020, harboring germline PV in BRCA genes. Our analysis investigates the impact of hormone receptor status on clinical behavior and outcomes of breast cancer. The type and pattern of recurrence and survival outcomes (disease-free survival [DFS], breast cancer specific survival [BCSS] and overall survival [OS]) were first investigated according to hormone receptors expression (positive vs. negative), and then according to breast cancer subtype (luminal A-like vs. luminal B-like vs. triple-negative vs. HER2-positive breast cancer). Findings: From 78 centers worldwide, 4,709 BRCA carriers were included in this analysis, of whom 2,143 (45·5%) had hormone receptor-positive and 2,566 (54·5%) hormone receptor-negative breast cancer. Patients with hormone receptor-positive disease were more likely to harbor BRCA2 PV while less frequently had grade 3 tumors and nodal involvement. Median follow-up was 7·9 (interquartile range [IQR] 4·5-12·6) years. The rate of distant recurrences was higher in patients with hormone receptor-positive breast cancer (13·1% vs. 9·6%, p<0·001), while the rate of second primary breast cancer was lower (9·1% vs. 14·7%, p<0·001) when compared to patients with hormone receptor-negative disease. The 8-years DFS was 65·8% in patients with hormone receptor-positive and 63·4% in those with hormone receptor-negative breast cancer. The hazard ratio of hormone receptor-positive vs. negative disease changed over time for DFS, BCSS, and OS (p<0·05 for interactions of hormone receptor status and survival time). Among the 4,363 patients eligible for subtypes analysis, 612 (14·0%) had luminal A-like, 1,038 (23·8%) luminal B-like, 2,373 (54·4%) triple-negative and 340 (7·8%) HER2-positive breast cancer. Patients with Luminal A-like breast cancer had the worst long-term prognosis in terms of DFS compared to all the other subgroups (8-years DFS: 60·8% in luminal A-like vs. 63·5% in triple-negative vs. 65·5% in HER2-positive and 69·7% in luminal B-like subtype). Interpretation: In young BRCA PV carriers with early breast cancer, hormone receptor status did not appear to be a positive prognostic factor. The differences in pattern of recurrence and second primary breast cancer among hormone receptor-positive vs. negative disease warrants consideration in counseling patients on treatment, follow-up strategies and indication for risk-reducing surgery. Funding: Associazione Italiana per la Ricerca sul Cancro (AIRC)Declaration of Interest: KP reported receiving honoraria for consultations/lectures/training/ clinical trials and payment of conferences fees from AstraZeneca, Gilead, Roche, Novartis, Eli Lilly, Pfizer, MSD, Teva, Egis, and Vipharm. KP reported receiving research grants (to his institution) from MSD and Sanofi; speaker fees and honoraria for consultancy and advisory board functions from AstraZeneca, Eli Lilly, Exact Sciences, Focus Patient, Gilead, Menarini, MSD, Novartis, Pfizer, Roche, and Seagen; speaker fees and honoraria for consultancy and advisory board functions (to his institution) from AstraZeneca, Eli Lilly, Exact Sciences, Gilead, MSD, Novartis, Pfizer, Roche, and Seagen; stock options from Need Inc; and travel grants from AstraZeneca, Novartis, Pfizer, PharmaMar, and Roche. JB reported receiving research grants (to his institution) from Eli Lilly, Novartis, Roche, AstraZeneca, Paxman Coolers, Samsung Bioepis, and Sun Pharma; conducting nonremunerated advisory board activities for Novartis; and having leadership roles with the Immuno-Oncology Society of India, the Indian Society of Medical and Paediatric Oncology, the Teenage and Young Cancer Association, ESMO, and the Society for Immunotherapy of Cancer. EA reported Consultancy fee or honoraria from Eli Lilly, Sandoz, AstraZeneca. Research grant to Institution from Gilead. Support for attending medical conferences from: Novartis, Roche, Eli Lilly, Genetic, Istituto Gentili, Daiichi Sankyo, AstraZeneca (all outside the submitted work). AT reported having an advisory role for Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Gilead, and MSD; receiving speaker honoraria from Lilly, Novartis, and Pfizer; and receiving travel grants from Gilead and Daiichi Sankyo. CRJ reported having an advisory role for Bristol Myers Squibb, Roche, and Theramex; receiving speaker honoraria (to her institution) from Novartis, Organon, and Theramex; and receiving research funding (to her institution) from Bayer Healthcare. GC reported personal fees for advisory board membership from AstraZeneca, BMS, Celcuity, Daiichi Sankyo, Ellipsis, Exact Sciences, Lilly, Merck, Pfizer, Roche and Veracyte; personal fees as an invited speaker from AstraZeneca, Daiichi Sankyo, Novartis, Pfizer and Roche; personal fees for a writing engagement from Pfizer; an institutional research grant from Merck for an investigatorinitiated trial; institutional funding for phase I studies from Astellas, AstraZeneca, Blueprint Medicine, BMS, Daiichi Sankyo, Kymab, Novartis, Philogen, Relay Therapeutics (coordinating PI), Roche and Sanofi; non-remunerated roles as Advisor for the Ministry of Health at the Italian National Health Council; as Chair of the ESMO Clinical Practice Guidelines Committee; as a member of the scientific council at Europa Donna, of the advisory council for EUSOMA and of the Board of Directors at Lega Italiana Lotta ai Tumori; and a non-remunerated advisory role at Fondazione Beretta. SPS reported independent grant from Pfizer, consulting fees from MSD, Roche, Gilead, Pfizer, Astra Zeneca, Lily, Stemline, Daichi Sankyo; Payment or honoraria from MSD, Roche, Gilead, Pfizer, Astra Zeneca, Lily, Stemline; Support for attending meetings and/or travel from Gilead, Pfizer; Participation on a Data Safety Monitoring Board or Advisory Board for Lily, Astra Zeneca; Leadership or fiduciary role in European Society of Medical Oncolology (ESMO). WC reported receiving honoraria from Pfizer, Merck, Eisai, and AstraZeneca. CV reported having an advisory role for Novartis, Eli Lilly, Daiichi Sankyo, and Pfizer; consultancy for Eli Lilly; receiving research grants (to his institution) from Roche; and receiving honoraria as a speaker from Novartis, Eli Lilly, Istituto Gentili, and Accedemia di Medicina. MVD reported Consulting fees from Lilly, Pfizer, Novartis, Seagen, Gilead, Roche, Daiichi-Sankyo, Exact Sciences, MSD; Payment or honoraria from Lilly; Patents planned, issued or pending: EP20382679.7. LDM reported Payment or honoraria from Astra Zeneca; Support for attending meetings and/or travel from Astra Zeneca, MSD. FP reported having an advisory role for and receiving speaker honoraria, travel grants, and research grants from Amgen, AstraZeneca, Daichii Sankyo, Celgene, Eisai, Eli Lilly, Exact Sciences, Gilead, Ipsen, Menarini, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Seagen, Takeda, and Viatris. AF reported independent grants or contracts from Pfizer, Gilead; consulting fees from Roche, Novartis, Lilly, Pfizer, MSD, Dompè, Pierre Fabre , Sophos, Gilead, Seagen, Astra Zeneca, Exact Science; Payment or honoraria from Roche, Novartis, Lilly, Pfizer, MSD, Pierre Fabre, Gilead, Seagen, Astra Zeneca, Exact Science; Support for attending meetings and/or travel from Roche, Novartis, Lilly, Pfizer, MSD, Pierre Fabre, Gilead, Seagen, Astra Zeneca, Exact Science; Participation on a Data Safety Monitoring Board or Advisory Board for Roche, Novartis, Lilly, Pfizer, MSD, Gilead, Seagen, Astra Zeneca, Exact Science; Leadership or fiduciary role in European Society of Medical Oncolology (ESMO), Associazione Italiana Oncologia Medica (AIOM). SLG reports Grants or contracts to the institution from AstraZeneca/Daiichi Sankyo, Novartis, Daiichi Sankyo; Consulting fees from Pfizer, SeaGen, AstraZeneca, DaiichiSankyo, Gilead Sciences, Menarini Stemline, Genentech, Novartis, Lilly/Loxo@Lilly; Payment or honoraria from The Academy for Healthcare Learning, DAVA Oncology, MJH Life Sciences, WebMD/Medscape, IntegrityCE, MedPage Today, MedIQ, Medical Educator Consortium, Remedy Media, Research to Practice. Stock or stock options of HCA Healthcare; Medical Adivsor to Dr. Susan Love Foundation for Breast Cancer Research. IW reported consulting fees from Pfizer, Astra Zeneca, Seagen; Payment or honoraria from Astra Zeneca, Lilly, Pfizer, Roche, Seagen, Gilead, Daiichi Sankyo; Support for attending meetings and/or travel from Roche, Lilly; Leadership or fiduciary role for breast group of the German Cancer Society, Breast guideline (S3-guideline). RD reported consulting fees from Exact Sciences, Gilead, Pfizer, Novartis, AstraZeneca; Payment or honoraria from Exact Sciences, Gilead, Pfizer, Novartis, AstraZeneca; Support for attending meetings and/or travel from Gilead, Pfizer; Participation on a Data Safety Monitoring Board or Advisory Board for Gilead, Pfizer, Sanofi. HLP reported Payment or honoraria from Daiichi Sankyo. VS reported Payment or honoraria from Novartis, Gentili, Accord, Daiichi Sankyo; Support for attending meetings and/or travel from Sophos, PharmaExtracta, Novartis; Leadership or fiduciary role for Associazione Italiana di Oncologia Medica (AIOM). EdA reported honoraria and/or advisory board from Roche/GNE, Novartis, SeaGen, Zodiac, Libbs, Pierre Fabre, Lilly, AstraZeneca, MSD, Gilead Sciences; Travel grants from Roche/GNE and AstraZeneca; Research grant to my institution from Roche/GNE, Astra-Zeneca, and GSK/Novartis, Gilead Sciences; Non-financial: ESMO director of Membership 2023-2025, BSMO President 2023-2026. EB reported receiving research funding (to her institution) from Gilead; speaker fees from Eli Lilly. ML reported having an advisory role for Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Gilead, MSD, Pierre Fabre, and Exact Sciences; receiving speaker honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Libbs, Daiichi Sankyo, Takeda, Knight, Ipsen, and AstraZeneca; receiving travel grants from Gilead, Roche, and Daiichi Sankyo; receiving research funding (to his institution) from Gilead; and having nonfinancial interests as the chair of the European Society for Medical Oncology (ESMO) Young Oncologists Committee (YOC) and as a member of the national council of the Italian Association of Medical Oncology. All the other authors declare no conflict of interests.Ethical Approval: The Institut Jules Bordet (Brussels, Belgium) sponsored the study and acted as central ethics committee. Whenever required by country and/or local regulations, the study received approval at participating centers by the local, regional, or national Institutional Review Board.
