PD-L1 expression and FGFR-mutations among Danish patients diagnosed with metastatic urothelial carcinoma: A retrospective and descriptive study.

Checkpoint inhibitors have changed the treatment landscape of advanced urothelial carcinoma (mUC), and recently, a fibroblast-growth-factor-receptor (FGFR) inhibitor has been introduced. This study aimed at estimating programmed death-ligand 1 (PD-L1) expression in primary tumors (PTs) and the PD-L1 expression concordance between PTs and paired metastases in 100 patients with UC managed in the real-world setting. Further, the aim was to investigate FGFR1-3 aberrations and the correlation between FGFR1-3 aberrations and PD-L1 expression. PD-L1 immunohistochemistry was performed on 100 formalin-fixed paraffin-embedded archival primary UC samples and 55 matched metastases using the 22C3 PD-L1 assay. PD-L1 expression was determined by the combined positive score, considered positive at ≥10. Targeted next-generation sequencing on the S5+/Prime System with the Oncomine Comprehensive Assay version 3 was used to detect FGFR1-3 aberrations in PTs. We found that 29 of 100 PTs had positive PD-L1 expression. The PD-L1 concordance rate was 71%. FGFR1-3 aberrations were observed in 18% of PTs, most frequently FGFR3 amplifications or mutations. We found no association between FGFR1-3 aberrations and PT PD-L1 expression (p = 0.379). Our data emphasize the need for further studies in predictive biomarkers.

Postmastectomy radiotherapy in high-risk breast cancer patients given adjuvant systemic therapy. A 30-year long-term report from the Danish breast cancer cooperative group DBCG 82bc trial.

BACKGROUND: Between 1982 and 1990 the Danish Breast Cancer Cooperative Group (DBCG) conducted a randomized trial in high-risk pre- and postmenopausal (<70 years) breast cancer patients comparing mastectomy plus adjuvant systemic therapy alone versus the same treatment plus postoperative irradiation. AIM: To present a comprehensive analysis of the complete DBCG 82bc study with a 30-year long-term follow-up of the cancer therapeutic effect and survival, together with an additional focus on the potential long-term life-threatening morbidity related to cardiac irradiation and/or the risk of secondary cancer induction. METHODS: A total of 3083 patients with pathological stage II and stage III breast cancer were after mastectomy randomly assigned to receive adjuvant systemic therapy and postoperative irradiation to the chestwall and regional lymph nodes (1538 pts), or adjuvant systemic therapy alone (1545 pts). Pre- and menopausal patients (DBCG 82b) received 8-9 cycles of CMF with an interval of 4 weeks, whereas postmenopausal patients (DBCG 82c) received tamoxifen 30 mg daily for one year. The median follow-up time was 34 years. The primary endpoints were loco-regional recurrence (LRR) and overall mortality, and the secondary endpoints were distant metastasis, breast cancer mortality, and irradiation related late morbidity. RESULTS: Overall the 30-year cumulative incidence of loco-regional recurrence was 9% in irradiated patients versus 37% in non-irradiated patients who received adjuvant systemic therapy alone (HR: 0.21 [95% cfl 0.18-0.26]). Distant metastasis probability at 30 years was 49% in irradiated patients compared to 60% in non-irradiated (HR: 0.77 [0.70-0.84]). Consequently, these figures resulted in a reduced breast cancer mortality: 56% vs 67% (HR: 0.75 [0.69-0.82], and overall mortality (81% vs 86% at 30 years (p < 0.0001), HR: 0.83 [0.77-0.90] in favor of irradiation. Radiotherapy did not result in any significant excess death of other courses, such as ischemic heart disease, HR: 0.82 [0.58-1.18]; nor secondary lung cancer HR: 1.44 [0.92-2.24], or other non-cancer related death HR: 1.15 [0.92-1.45]. CONCLUSION: The study definitely demonstrate that optimal long-term treatment benefit of high-risk breast cancer can only be achieved if both loco-regional and systemic tumor control are aimed for. Therefore, radiotherapy has an important role in the multidisciplinary treatment of breast cancer. The PMRT treatment did not result in excess ischemic heart damage, nor in other non-breast cancer related death.

Risk of second non-breast cancer among patients treated with and without postoperative radiotherapy for primary breast cancer: A systematic review and meta-analysis of population-based studies including 522,739 patients.

BACKGROUND AND PURPOSE: Radiotherapy plays an essential role in early breast cancer treatment, but is also associated with an increased risk of second malignancies decades after the exposure. MATERIALS AND METHODS: We systematically searched the data-bases Medline/Pubmed, Cochrane, Embase, and Cinahl, for cohort studies estimating the risk of second non-breast cancer after primary breast cancer. Every included study was to report the standardized incidence ratio [SIR] of second cancers, comparing the risk among either irradiated or unirradiated female breast cancer patients to the risk of the general female population. From each study the SIRs were extracted and then pooled using random-effects meta-analysis. SIRs were pooled as an overall estimate and according to time since breast cancer diagnosis. RESULTS: 22 studies were eligible for inclusion, comprising 245,575 irradiated and 277,164 non-irradiated women. Irradiated patients had an overall increased risk of second non-breast cancer, with a SIR of 1.23 (95% confidence interval [CI] 1.12-1.36). For non-irradiated patients the SIR was 1.08 (95% CI, 1.03-1.13). For irradiated patients the incidence of second cancers including the lung, esophagus, thyroid and connective tissues progressively increased over time, peaking at 10-15years following breast cancer diagnosis. Summary estimates at ⩾15years after breast cancer irradiation were 1.91 for lung, 2.71 for esophagus, 3.15 for thyroid and 6.54 at ⩾10years for second sarcomas. Non-irradiated patients had no increased risk of second lung or esophagus cancer, neither overall nor over time. For non-irradiated patients' risk of second thyroid cancer (SIR 1.21) and sarcomas (SIR 1.42) were increased overall, but with no remaining risk ⩾10 after breast cancer. CONCLUSION: Radiotherapy for breast cancer is associated with an excess risk of second non-breast cancer, overall and in organs adjacent to the previous treatment fields. The growing number of long-term survivors after breast cancer highlights the need for an improved individualized approach toward identifying patients with an expected benefit from radiation and patients with no added radiation-benefit.

Risk of second non-breast cancer after radiotherapy for breast cancer: a systematic review and meta-analysis of 762,468 patients.

BACKGROUND AND PURPOSE: Radiotherapy for breast cancer both decreases loco-regional recurrence rates and improves overall survival. However, radiotherapy has also been associated with increased second cancer risk at exposed sites. In this meta-analysis, we estimated the risk of second non-breast cancers after radiotherapy for breast cancer. MATERIAL AND METHODS: The databases Medline/Pubmed, Cochrane, Embase and Cinahl were systematically searched, for cohort studies on second cancer after radiotherapy for breast cancer, from inception to August 1st 2013. Included studies were to report the relative risk (RR) of second cancers comparing irradiated female breast cancer patients to unirradiated patients. Primary endpoints were all second non-breast-cancers and second cancers of the lung, esophagus, thyroid and second sarcomas. RRs were pooled using random-effects meta-analysis. RESULTS: Thirteen studies comprising 762,468 breast cancer patients were included in the meta-analysis. Five or more years after breast cancer diagnosis radiotherapy was significantly associated with an increased risk of second non-breast cancer RR 1.12 (95% confidence interval [CI] 1.06-1.19), second cancer of the lung RR 1.39 (95% CI 1.28-1.51), esophagus RR 1.53 (95% CI 1.01-2.31) and second sarcomas RR 2.53 (95% CI 1.74-3.70). The risk increased over time, and was highest 15 or more years after breast cancer diagnosis, for second lung RR 1.66 (95% CI 1.36-2.01) and second esophagus cancer RR 2.17 (95% CI 1.11-4.25). There was no significant association between radiotherapy and second thyroid cancer. CONCLUSIONS: Radiotherapy for breast cancer is significantly associated with increased risks of second non-breast cancer, overall and in organs adjacent to the previous treatment fields. Despite a relative small absolute risk, the growing number of long-time survivors after breast cancer warrants the need for normal tissue sparing radiotherapy techniques.

Risk of second primary lung cancer in women after radiotherapy for breast cancer.

BACKGROUND: Several epidemiological studies have reported increased risks of second lung cancers after breast cancer irradiation. In this study we assessed the effects of the delivered radiation dose to the lung and the risk of second primary lung cancer. METHODS: We conducted a nested case-control study of second lung cancer in a population based cohort of 23,627 early breast cancer patients treated with post-operative radiotherapy from 1982 to 2007. The cohort included 151 cases diagnosed with second primary lung cancer and 443 controls. Individual dose-reconstructions were performed and the delivered dose to the center of the second lung tumor and the comparable location for the controls were estimated, based on the patient specific radiotherapy charts. RESULTS: The median age at breast cancer diagnosis was 54 years (range 34-74). The median time from breast cancer treatment to second lung cancer diagnosis was 12 years (range 1-26 years). 91% of the cases were categorized as ever smokers vs. 40% among the controls. For patients diagnosed with a second primary lung cancer five or more years after breast cancer treatment the rate of lung cancer increased linearly with 8.5% per Gray (95% confidence interval=3.1-23.3%; p<0.001). This rate was enhanced for ever smokers with an excess rate of 17.3% per Gray (95% CI=4.5-54%; p<0.005). CONCLUSIONS: Second lung cancer after radiotherapy for early breast cancer is associated with the delivered dose to the lung. Although the absolute risk is relative low, the growing number of long-time survivors after breast cancer treatment highlights the need for advances in normal tissue sparing radiation techniques.

Second primary cancers after adjuvant radiotherapy in early breast cancer patients: a national population based study under the Danish Breast Cancer Cooperative Group (DBCG).

BACKGROUND AND PURPOSE: To analyze the long-term risk of second primary solid non-breast cancer in a national population-based cohort of 46,176 patients treated for early breast cancer between 1982 and 2007. PATIENTS AND METHODS: All patients studied were treated according to the national guidelines of the Danish Breast Cancer Cooperative Group. The risk of second primary cancers was estimated by Standardised incidence ratios (SIRs) and multivariate Cox regression models were used to estimate adjusted hazard ratios (HR) among irradiated women compared to non-irradiated. All irradiated patients were treated on linear accelerators. Second cancers were a priori categorized into two groups; radiotherapy-associated- (oesophagus, lung, heart/mediastinum, pleura, bones, and connective tissue) and non-radiotherapy-associated sites (all other cancers). RESULTS: 2358 second cancers had occurred during the follow-up. For the radiotherapy-associated sites the HR among irradiated women was 1.34 (95% CI 1.11-1.61) with significantly increased HRs for the time periods of 10-14 years (HR 1.55; 95% CI 1.08-2.24) and ≥ 15 years after treatment (HR 1.79; 95% CI 1.14-2.81). There was no increased risk for the non-radiotherapy-associated sites (HR 1.04; 95% CI 0.94-1.1). The estimated attributable risk related to radiotherapy for the radiotherapy-associated sites translates into one radiation-induced second cancer in every 200 women treated with radiotherapy. CONCLUSIONS: Radiotherapy treated breast cancer patients have a small but significantly excess risk of second cancers.