A Phase II Trial of Stereotactic Body Radiation Therapy and Androgen Deprivation for Oligometastases in Prostate Cancer (SBRT-SG 05).

PURPOSE: SBRT-Spanish Group-05 (ClinicalTrials.gov.Identifier: NCT02192788) is a collaborative (SBRT-SG, Grupo de Investigación Clínica en Oncología Radioterápica, and Sociedad Española de Oncología Radioterápica) prospective multicenter phase II trial testing stereotactic body radiation therapy (SBRT) and androgen deprivation therapy (ADT) in patients with oligorecurrent prostate cancer. METHODS AND MATERIALS: Two cohorts of patients with prostate cancer in an oligorecurrent stage (hormone-sensitive in the principal cohort and castration-resistant in the exploratory cohort) were assigned to receive ADT and SBRT for at least 24 months from the time of the enrollment. Concomitant treatment with chemotherapy, abiraterone, or enzalutamide was not allowed. Oncologic outcomes were assessed in both cohorts. Toxicity was prospectively analyzed. RESULTS: From 2014 to 2019, 81 patients with a total of 126 lesions from 14 centers met the inclusion criteria, 14 of whom were castration-resistant. With a median follow-up of 40 months (12-58 months), 3-year local recurrence-free survival was 92.5% (95% CI, 79.9%-96.3%) and 85.7% (95% CI, 48.2%-95.6%) in the principal and exploratory cohorts, respectively. In the principal cohort, biochemical relapse-free survival and metastasis progression-free survival at 1, 2, and 3 years were 91% (95% CI, 81%-95.8%), 73.7% (95% CI, 61.1%-82.8%), 50.6% (95% CI, 36.2%-63.3%), and 92% (95% CI, 83%-97%), 81% (95% CI, 70%-89%), and 67% (95% CI, 53%-77%), respectively. In the exploratory cohort, metastasis progression-free survival at 1, 2, and 3 years was 64% (95% CI, 34%-83%), 43% (95% CI, 18%-66%), and 26% (95% CI, 7%-51%), respectively. None of the patients developed grade III or higher toxicity or symptoms related to local progression, and only 2 (2.4%) patients developed grade II toxicity. CONCLUSIONS: The combination of SBRT and ADT is safe and shows favorable clinical outcomes in patients with hormone-sensitive and castration-resistant prostate cancer. Validation studies are needed in patients with castration-resistant prostate cancer.

Liquid biopsy to personalize treatment for metastatic prostate cancer.

Liquid biopsy is an innovative approach that provides a more complete understanding of treatment response and prognosis in monitoring metastatic prostate cancer. It complements invasive tissue biopsy and involves the assessment of various biomarkers in body fluids such as blood, semen, and urine. Liquid biopsy analyzes circulating tumor cells, extracellular vesicles, circulating tumor DNA, and the secretome. This is particularly important given the heterogeneity of prostate cancer and the need for better prognostic biomarkers. Liquid biopsy can personalize the treatment of homonosensitive and castration-resistant metastatic prostate cancer by acting as a predictive and prognostic tool. This review discusses various biomarkers, assay techniques, and potential applications in daily clinical practice, highlighting the exciting possibilities that this emerging field holds for improving patient outcomes.

Feasibility and Acute Toxicity of Hypo-Fractionated Radiotherapy on 0.35T MR-LINAC: The First Prospective Study in Spain.

This observational, descriptive, longitudinal, and prospective basket-type study (Registry #5289) prospectively evaluated the feasibility and acute toxicity of hypo-fractionated radiotherapy on the first 0.35T MR-LINAC in Spain. A total of 37 patients were included between August and December 2023, primarily with prostate tumors (59.46%), followed by pancreatic tumors (32.44%). Treatment regimens typically involved extreme hypo-fractionated radiotherapy, with precise dose delivery verified through quality assurance measures. Acute toxicity assessment at treatment completion revealed manageable cystitis, with one case persisting at the three-month follow-up. Gastrointestinal toxicity was minimal. For pancreatic tumors, daily adaptation of organ-at-risk (OAR) and gross tumor volume (GTV) was practiced, with median doses to OAR within acceptable limits. Three patients experienced gastrointestinal toxicity, mainly nausea. Overall, the study demonstrates the feasibility and safety of extreme hypo-fractionated radiotherapy on a 0.35T MR-LINAC, especially for challenging anatomical sites like prostate and pancreatic tumors. These findings support the feasibility of MR-LINAC-based radiotherapy in delivering precise treatments with minimal toxicity, highlighting its potential for optimizing cancer treatment strategies.

Management of lateral pelvic lymph nodes in rectal cancer: Is it time to reach an Agreement?

In this editorial, we proceed to comment on the article by Chua et al, addressing the management of metastatic lateral pelvic lymph nodes (mLLN) in stage II/III rectal cancer patients below the peritoneal reflection. The treatment of this nodal area sparks significant controversy due to the strategic differences followed by Eastern and Western physicians, albeit with a higher degree of convergence in recent years. The dissection of lateral pelvic lymph nodes without neoadjuvant therapy is a standard practice in Eastern countries. In contrast, in the West, preference leans towards opting for neoadjuvant therapy with chemoradiotherapy or radiotherapy, that would cover the treatment of this area without the need to add the dissection of these nodes to the total mesorectal excision. In the presence of high-risk nodal characteristics for mLLN related to radiological imaging and lack of response to neoadjuvant therapy, the risk of lateral local recurrence increases, suggesting the appropriate selection of strategies to reduce the risk of recurrence in each patient profile. Despite the heterogeneous and retrospective nature of studies addressing this area, an international consensus is necessary to approach this clinical scenario uniformly.

Radiotherapy for Metastatic Epidural Spinal Cord Compression with Increased Doses: Final Results of the RAMSES-01 Trial.

Patients with metastatic epidural spinal cord compression (MESCC) and favorable survival prognoses may benefit from radiation doses exceeding 10 × 3.0 Gy. In a multi-center phase 2 trial, patients receiving 15 × 2.633 Gy (41.6 Gy10) or 18 × 2.333 Gy (43.2 Gy10) were evaluated for local progression-free survival (LPFS), motor/sensory functions, ambulatory status, pain, distress, toxicity, and overall survival (OS). They were compared (propensity score-adjusted Cox regression) to a historical control group (n = 266) receiving 10 × 3.0 Gy (32.5 Gy10). In the phase 2 cohort, 50 (of 62 planned) patients were evaluated for LPFS. Twelve-month rates of LPFS and OS were 96.8% and 69.9%, respectively. Motor and sensory functions improved in 56% and 57.1% of patients, and 94.0% were ambulatory following radiotherapy. Pain and distress decreased in 84.4% and 78.0% of patients. Ten and two patients experienced grade 2 and 3 toxicities, respectively. Phase 2 patients showed significantly better LPFS than the control group (p = 0.039) and a trend for improved motor function (p = 0.057). Ambulatory and OS rates were not significantly different. Radiotherapy with 15 × 2.633 Gy or 18 × 2.333 Gy was well tolerated and appeared superior to 10 × 3.0 Gy.

A Phase 2 Randomized Open-label Study of Oral Darolutamide Monotherapy Versus Androgen Deprivation Therapy in Men with Hormone-sensitive Prostate Cancer (EORTC-GUCG 1532).

BACKGROUND AND OBJECTIVE: Darolutamide is an androgen receptor inhibitor that increases overall survival in combination with androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive and nonmetastatic castration-resistant prostate cancer (PCa). This phase 2 study assessed the efficacy and safety of darolutamide as monotherapy without ADT in patients with eugonadal testosterone levels. METHODS: This was a 24-wk, open-label, randomized study of patients with hormone-sensitive, histologically confirmed PCa requiring gonadotropin-releasing hormone (GnRH); an Eastern Cooperative Oncology Group performance status score of 0/1; and life expectancy >1 yr. All patients received darolutamide 600 mg bid or a commercially available GnRH analog. The primary endpoint is a prostate-specific antigen (PSA) response, defined as a ≥80% decline at week 24 relative to baseline in the darolutamide study arm. The GnRH arm is used as an internal control. The secondary endpoints included changes in T levels, safety/tolerability, and quality of life. KEY FINDINGS AND LIMITATIONS: Among 61 men enrolled, the median (range) age was 72 yr (53-86 yr); 42.6% of them had metastases. In the darolutamide arm, the evaluable population with available PSA values at baseline and week 24 consisted of 23 patients. Twenty-three (100%) evaluable darolutamide patients achieved a PSA decline of >80% at week 24 (primary endpoint), with a median (range) decrease of -99.1% (-91.9%, -100%). Serum T levels increased by a median (range) of 44.3 (5.7-144.0) at week 24, compared with baseline. In the darolutamide arm, 48.4% of men reported drug-related adverse events (AEs; mostly grade 1 or 2). The most frequent treatment-emergent AEs included gynecomastia (35.5%), fatigue (12.9%), hot flush (12.9%), and hypertension (12.9%). Health-related quality of life measures are descriptive, and GnRH arm results will be presented as an internal reference. CONCLUSIONS AND CLINICAL IMPLICATIONS: Darolutamide monotherapy was associated with a significant PSA response in nearly all men with hormone-naïve PCa. Testosterone-level changes and most common AEs (gynecomastia, fatigue, hypertension, and hot flush) were consistent with potent androgen receptor inhibition. PATIENT SUMMARY: In this study, we report the first use of darolutamide, a novel antiandrogen, as monotherapy without androgen deprivation therapy (ADT). The study shows that darolutamide induce a profound suppression of prostate-specific antigen in all patients, with a safety profile different from that of ADT.

Docetaxel Provides Oncological Benefits in the Era of New-Generation Androgen Receptor Inhibitors - or Is Three a Crowd?

In recent years, several systemic therapies have been introduced for metastatic hormone-sensitive prostate cancer, including androgen deprivation therapy (ADT) combined with docetaxel (Doc) and/or new-generation androgen receptor signaling inhibitors (ARSI). Trials evaluating ADT + ARSI have consistently demonstrated an overall survival (OS) benefit for doublet therapy over ADT alone. Similarly, the STOPCaP meta-analysis showed an OS benefit in favor of ADT + Doc versus ADT alone. ARSI, Doc, and ADT have different antitumor mechanisms, thus potentiating the effect of combination therapy. Two randomized trials showed that the addition of ARSI to ADT + Doc improves OS, especially for synchronous high-volume disease. However, the real question about triplet therapy remains unanswered: whether combining Doc with ARSI improves outcomes compared to ADT + ARSI. As there are no head-to-head comparisons, this narrative review aims to summarize the current evidence regarding triplet therapy versus doublet therapy including ADT+ ARSI.

Role of Radiotherapy and Hormone Therapy in Patients with Node-Positive Locally Advanced Prostate Cancer

New-generation imaging techniques and the increasing use of surgery in high-risk prostate cancer (PCa) allow usto detect many cases of nodal disease at initial diagnosis or after resection. The treatment of PCa with pathologic regional nodeshas evolved from the exclusive use of systemic therapy to its combination with locoregional treatment. It can also represent abenefit in the overall survival. However, the evidence from randomised studies is limited. Thus, we review the most relevantresults in this scenario.Materials and Methods: A literature search was conducted in MEDLINE, PubMed, EMBASE, Clinical-Trials.gov and Webof Science on January 2023 to review node-positive PCa by considering the relevant literature on this topic published with norestrictions on date and language. The search keywords used were “Prostatic Neoplasms” (MeSh) and “Node-positive” (TextWord) and “Radiotherapy” (MeSh) and (“Androgen Antagonists” (MeSh) or “Antineoplastic Agents, Hormonal” (MeSh)), whichare indexed within the Medical Subject Headings database.Results: The management of node-positive PCa has no clear definitive consensus at the initial disease diagnosis or after surgery.However, in this review, we summarise the existing literature for the management of these patients in both scenarios, consideringimaging tests, radiotherapy, hormone therapy and second-generation hormonal treatments.Conclusions: The combination of radiotherapy and androgen-deprivation therapy is the treatment of choice. The addition ofsecond-generation hormone therapy, plus the intensification of radiotherapy schedules, will likely change the treatment paradigm for these patients. (AU)

Prostate Cancer: Management of Biochemical Recurrence after Surgery

Radical prostatectomy (RP) is one of the primary treatment options for localised prostate cancer (PCa). Despite its curativeintent, 1/3 of patients will experience biochemical recurrence (BCR) during follow-up. Experts have devoted efforts to associatethe influence of each individual factor with the risk of BCR to select the optimal treatment for each patient. Optimal managementmust aim to find a balance between delaying the onset of metastatic disease and overtreating an indolent disease with treatmentsthat can affect quality of life of the patients. Thus far, effective treatment options for men with BCR remain controversial interms of ideal treatment timing (adjuvant vs. salvage), radiotherapy (RT) fields and doses, selection and duration of systemictherapy and potential synergies between treatments and their therapeutic sequencing. Next-generation imaging techniques, suchas Prostate-Specific Membrane Antigen Positron Emission Tomography, are used for early detection of disease progression andexact site of recurrence or progression, thereby enhancing decision making for future disease management. In this review, weevaluate available evidence of controversial topics regarding BCR after RP and explore future directions, such as prognosticand/or predictive factors of response, genetic panels, second-generation hormone treatments, ultra-hypofractionated RT andongoing clinical trials in this clinical scenario. (AU)

Jorge clinical study: 10-year outcomes of risk-adapted radiotherapy defined by multiparametric MRI for prostate cancer.

PURPOSE: To analyze the 10-year biochemical relapse-free survival (BRFS), locoregional relapse-free survival (LRFS), metastasis-free survival (MFS), and overall survival (OS) in patients diagnosed with localized prostate adenocarcinoma treated with radiotherapy (RT) ± androgen deprivation therapy (ADT), according to the risk groups based on multiparametric magnetic resonance imaging (mpMRI) instead of digital rectal exam (DRE). METHODS: We retrospectively evaluated 140 consecutive patients diagnosed with localized prostate adenocarcinoma, stratified into different risk groups-low (LR), intermediate (IR), and high (HR) by mpMRI results. RESULTS: After a median follow-up of 104 months, in LR group (n = 15), 10-year BRFS was 86.7%, 10-year LRFS was 86.7%, 10-year MFS was 93.3%, and 10-year OS was 100%. In IR group (n = 80), 10-year BRFS was 80.5%, 10-year LRFS was 86.1%, 10-year MFS was 92.6%, and 10-year OS was 76%. In HR group (n = 45), 10-year BRFS was 72.8%, 10-year LRFS was 78.7%, 10-year MFS was 82.1%, and 10-year OS was 77% (2 deaths from prostate cancer). According to mpMRI results, 36 (25.7%) patients change the risk group and 125 (89.28%) patients change the TNM stage. There was a trend for higher metastatic relapse in patients who switched from IR to HR (due to mpMRI) versus the patients who remained in the IR (20%, vs. 1.81% p = 0.059). Multivariate analysis showed that locoregional relapse was strongly associated with distant relapse (OR = 9.28; 95%CI: 2.60-33.31). There were no cases of acute grade 3 toxicity. Late grade 3 genitourinary, gastrointestinal, and sexual toxicity were 2.8%, 0.7%, and 1.2%, respectively. CONCLUSION: This is the first study with a 10-year median follow-up of patients diagnosed with localized prostate cancer treated with radiotherapy according to the risk groups established by mpMRI. Our findings show that mpMRI is a key tool to diagnose and establish risk groups in these patients, to optimize their treatment.

Total neoadjuvant therapy approach for the treatment of locally advanced rectal cancer. Where do we stand?

BACKGROUND: for the management of locally advanced rectal cancer (LARC), initial treatment with neoadjuvant chemoradiotherapy followed by surgery and chemotherapy in selected patients is considered one of the recommended options by the main international clinical guidelines. Nonetheless, the administration of all chemotherapy before definitive treatment (total neoadjuvant therapy or TNT) is an optimal alternative with a growing level of evidence that must be evaluated in multidisciplinary boards. This review summarizes the available data and controversies in this scenario. SUMMARY: we have analyzed the characteristics of the main published studies that assess the use of TNT in patients with LARC, evaluating their inclusion criteria and distinguishing between the employed radiotherapy fractionations, systemic agents, timing, and the implications of these treatments in regard to surgery and long-term oncological results. Our aim is to describe the evidence that supports the use of a specific regime in everyday clinical practice. KEY POINTS: there is solid evidence for the use of TNT in patients with LARC. There is no data indicating the superiority of one specific TNT scheme among all the existing options. International clinical guidelines leave the door open to choose the most adequate treatment based on the clinical and pathological characteristics of each patient. This review shows the different approaches to TNT and assesses the best options based on clinical evidence.

Treatment of metastatic squamous cell carcinoma arising in sacrococcygeal pilonidal sinus: a case report series.

Background: Squamous cell carcinoma (SCC) arising in a sacrococcygeal pilonidal sinus is rare, with cases of metastatic disease being even rarer. Among published cases, almost none have reported on systemic treatment. Objective: This disease has a poorer prognosis than other forms of cutaneous SCC; therefore, our objective is to shed some light on the treatment of metastatic disease. Methods: We present a series of nine cases treated at a single center, four of whom received systemic treatment. Additionally, other previously reported cases of metastatic disease are included in an attempt to draw stronger conclusions. Results: Four patients were treated under several treatment regimens, with a median progression-free survival of only 2 months and two instances of partial response (18%). The best result was achieved with cemiplimab. Across all the cases, there was a trend toward a benefit of the use of systemic treatment (HR 0.41, 95% CI 0.15-1.12, p = 0.083; median overall survival 13 vs. 8 months). Limitations: Limitations include the significant lack of information on previously published cases and the extremely heterogeneous nature of the existing information. Conclusion: The initial systemic treatment should be an anti-PD-1, as with other SCCs. After progression on anti-PD-1, there is no strong evidence to support the recommendation of a specific treatment or sequence: options include cetuximab and/or chemotherapy (platinum, paclitaxel, 5-fluorouracyl).

PEACE V-Salvage Treatment of OligoRecurrent nodal prostate cancer Metastases (STORM): Acute Toxicity of a Randomized Phase 2 Trial.

BACKGROUND: Treatment recommendations for patients with limited nodal recurrences are lacking, and different locoregional treatment approaches are currently being used. OBJECTIVE: The aim of this trial is to compare metastasis-directed therapy (MDT) with or without elective nodal pelvic radiotherapy (ENRT). DESIGN, SETTING, AND PARTICIPANTS: PEACE V-Salvage Treatment of OligoRecurrent nodal prostate cancer Metastases (STORM) is an international, phase 2, open-label, randomized, superiority trial (ClinicalTrials.gov identifier: NCT03569241). Patients diagnosed with positron emission tomography-detected pelvic nodal oligorecurrence (five or fewer nodes) following radical local treatment for prostate cancer were randomized in a 1:1 ratio between arm A (MDT and 6 mo of androgen deprivation therapy [ADT]) and arm B (ENRT [25 × 1.8 Gy] with MDT and 6 mo of ADT). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We report the secondary endpoint acute toxicity, defined as worst grade ≥2 Common Terminology Criteria for Adverse Events v4.0 gastrointestinal (GI) or genitourinary (GU) toxicity within 3 mo of treatment. The chi-square test was used to compare toxicity between treatment arms. We also compare the quality of life (QoL) using the European Organisation for Research and Treatment of Cancer QLQ C30 and PR25 questionnaires. RESULTS AND LIMITATIONS: Between June 2018 and April 2021, 196 patients were assigned randomly to MDT or ENRT. Ninety-seven of 99 patients allocated to MDT and 93 of 97 allocated to ENRT received per-protocol treatment. Worst acute GI toxicity proportions were as follows: grade ≥2 events in three (3%) in the MDT group versus four (4%) in the ENRT group (p = 0.11). Worst acute GU toxicity proportions were as follows: grade ≥2 events in eight (8%) in the MDT group versus 12 (13%) in the ENRT group (p = 0.95). We observed no significant difference between the study groups in the proportion of patients with a clinically significant QoL reduction from baseline for any subdomain score area. CONCLUSIONS: No clinically meaningful differences were observed in worst grade ≥2 acute GI or GU toxicity or in QoL subdomains between MDT and ENRT. PATIENT SUMMARY: We found no evidence of differential acute bowel or urinary side effects using metastasis-directed therapy and elective nodal radiotherapy for the treatment of patients with a pelvic lymph node recurrence.

Prospective Assessment of Bone Metabolism Biomarkers and Survival in Metastatic Castration-resistant Prostate Cancer Patients Treated with Radium-223: The PRORADIUM Study.

BACKGROUND: Radium-223 is an active therapy option for bone metastatic castration-resistant prostate cancer (mCRPC). The lack of adequate biomarkers for patient selection and response assessment are major drawbacks for its use. OBJECTIVE: To assess the prognostic value of bone metabolism biomarkers (BMBs) in ra-223-treated mCRPC patients. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study of mCRPC patients treated with Ra-223 (PRORADIUM study: NCT02925702) was conducted. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The main objective of the study was to evaluate the association between high (≥median) baseline values in at least three bone formation (bone alkaline phosphatase [BAP] and C-terminal type-I collagen propeptide) and bone resorption (N-terminal telopeptide and pyridinoline) biomarkers, and survival. The independent prognostic value of each BMB was also assessed. The association with time to radiographic, clinical, and prostate-specific antigen (PSA) progression; time to skeletal-related events; and PSA response were secondary objectives. Multivariable (MV) Cox-regression models were evaluated. RESULTS AND LIMITATIONS: A total of 169 patients were included. Of the patients, 70.4% received Ra-223 in second/third line; 144 (85.2%) were Eastern Cooperative Oncology Group 0-1, 126 (74.6%) were in pain, and 80 (47.5%) had more than ten bone metastases. Sixty-seven (39.6%) patients had elevation in at least three BMBs. The median overall survival was 12.1 mo (95% confidence interval [CI]: 10-14.7). No association was observed with other treatment-related secondary outcome parameters. Patients with high values in three or more BMBs had significantly worse survival (9.9 vs 15.2 mo; hazard ratio [HR]: 1.8 [95% CI: 1.3-2.5]; p < 0.001) in the univariate analysis, but not independent in the MV analysis (HR: 1.33; 95% CI: 0.89-2; p = 0.181). High baseline BAP was the only biomarker associated with survival in the MV model (HR: 1.89; 95% CI: 1.28-2.79; p = 0.001). Addition of BAP to the MV clinical model increased the area under the receiver operating characteristic curve 2-yr value from 0.667 to 0.755 (p = 0.003). CONCLUSIONS: Biomarkers of bone formation, especially BAP, have prognostic value in mCRPC patients treated with radium-223. Its predictive value remains to be assessed, ideally in prospective, adequately powered, randomised clinical trials. PATIENT SUMMARY: In this study, we evaluate the role of bone metabolism biomarkers to help improve the use of radium-223 as therapy for advanced prostate cancer. We found that bone alkaline phosphatase may be a suitable tool.

Novel Approaches in the Systemic Management of High-Risk Prostate Cancer.

Locally advanced prostate cancer comprises approximately 20% of new prostate cancer diagnoses. For these patients, international guidelines recommend treatment with radiotherapy (RT) to the prostate in combination with long-term (2-3 years) androgen deprivation therapy (ADT), or radical prostatectomy in combination with extended pelvic lymph node dissection (PLND) as another treatment option for selected patients as part of multimodal therapy. Improvements in overall survival with docetaxel or an androgen receptor signaling inhibitor have been achieved in patients with metastatic castration sensitive or castration resistant prostate cancer. However, the role of systemic therapy combinations for high risk and/or unfavorable prostate cancer is unclear. In this context, the aim of this review is to assess the current evidence for systemic treatment combinations as part of primary definitive therapy in patients with high-risk localized prostate cancer.

Utility of CYP2D6 copy number variants as prognostic biomarker in localized anal squamous cell carcinoma.

BACKGROUND: Anal squamous cell carcinoma (ASCC) is an infrequent tumor whose treatment has not changed since the 1970s. The aim of this study is the identification of biomarkers allowing personalized treatments and improvement of therapeutic outcomes. METHODS: Forty-six paraffin tumor samples from ASCC patients were analyzed by whole-exome sequencing. Copy number variants (CNVs) were identified and their relation to disease-free survival (DFS) was studied and validated in an independent retrospective cohort of 101 ASCC patients from the Multidisciplinary Spanish Digestive Cancer Group (GEMCAD). GEMCAD cohort proteomics allowed assessing the biological features of these tumors. RESULTS: On the discovery cohort, the median age was 61 years old, 50% were males, stages I/II/III: 3 (7%)/16 (35%)/27 (58%), respectively, median DFS was 33 months, and overall survival was 45 months. Twenty-nine genes whose duplication was related to DFS were identified. The most representative was duplications of the CYP2D locus, including CYP2D6, CYP2D7P, and CYP2D8P genes. Patients with CYP2D6 CNV had worse DFS at 5 years than those with two CYP2D6 copies (21% vs. 84%; p < .0002, hazard ratio [HR], 5.8; 95% confidence interval [CI], 2.7-24.9). In the GEMCAD validation cohort, patients with CYP2D6 CNV also had worse DFS at 5 years (56% vs. 87%; p = .02, HR = 3.6; 95% CI, 1.1-5.7). Mitochondria and mitochondrial cell-cycle proteins were overexpressed in patients with CYP2D6 CNV. CONCLUSIONS: Tumor CYP2D6 CNV identified patients with a significantly worse DFS at 5 years among localized ASCC patients treated with 5-fluorouracil, mitomycin C, and radiotherapy. Proteomics pointed out mitochondria and mitochondrial cell-cycle genes as possible therapeutic targets for these high-risk patients. PLAIN LANGUAGE SUMMARY: Anal squamous cell carcinoma is an infrequent tumor whose treatment has not been changed since the 1970s. However, disease-free survival in late staged tumors is between 40% and 70%. The presence of an alteration in the number of copies of CYP2D6 gene is a biomarker of worse disease-free survival. The analysis of the proteins in these high-risk patients pointed out mitochondria and mitochondrial cell-cycle genes as possible therapeutic targets. Therefore, the determination of the number of copies of CYP2D6 allows the identification of anal squamous carcinoma patients with a high-risk of relapse that could be redirected to a clinical trial. Additionally, this study may be useful to suggest new treatment strategies to increase current therapy efficacy.

Unravelling oligometastatic disease from the perspective of radiation and medical oncology. Part I: non-small cell lung cancer and breast cancer

Oligometastatic disease (OMD) defines a cancer status that is intermediate between localized and widely spread metastatic disease, and can be treated with curative intent. While diagnostic imaging tools have considerably improved in recent years, unidentified micrometastases can still evade current detection techniques, allowing the disease to progress. The various OMD scenarios are mainly defined by the number of metastases, the biological and molecular tumour profiles, and the timing of the development of metastases. Increasing knowledge has contributed to the earlier and improved detection of OMD, underlining the importance of early disease control. In view of increasing OMD detection rates in current real-world clinical practice and the lack of standardized evidence-based guidelines to treat this cancer status, a board of experts from the Spanish Societies of Radiation Oncology (SEOR) and Medical Oncology (SEOM) organized a series of sessions to update the current state-of-the-art on OMD from a multidisciplinary perspective, and to discuss how results from clinical studies might translate into promising treatment options. This expert review series summarizes what is known and what it is pending clarification in the context of OMD in the scenarios of non-small cell lung cancer and breast cancer (Part I), and prostate cancer and colorectal cancer (Part II), aiming to offer specialists a pragmatic framework to help improve patient management (AU)

Unravelling oligometastatic disease from the perspective of radiation and medical oncology. Part II: prostate cancer and colorectal cancer

Oligometastatic disease (OMD) defines a status of cancer that is intermediate between localized and widely spread metastatic disease, and can be treated with curative intent. While imaging diagnostic tools have considerably improved in recent years, unidentified micrometastases can still escape from current detection techniques allowing disease to progress. The variety of OMD scenarios are mainly defined by the number of metastases, the biological and molecular tumour profiles, and the timing of the development of metastases. Increasing knowledge has contributed to the earlier and improved detection of OMD, underlining the importance of an early disease control. Based on increasing detection rates of OMD in the current real clinical practice and the lack of standardized evidence-based guidelines to treat this cancer status, a board of experts from the Spanish Societies of Radiation Oncology (SEOR) and Medical Oncology (SEOM) organized a series of sessions to update the current state-of-the-art on OMD from a multidisciplinary perspective, and to discuss how results from clinical studies may translate into promising treatment options. This experts’ review series summarizes what is known and what it is pending clarification in the context of OMD in the scenarios of Non-Small Cell Lung Cancer and Breast Cancer (Part I), and Prostate Cancer and Colorectal Cancer (Part II), aiming to offer specialists a pragmatic framework that might contribute to the improved management of patients (AU)

Impact of concurrent tumour events on the prostate cancer outcomes of germline BRCA2 mutation carriers.

BACKGROUND: Several studies have reported the association of germline BRCA2 (gBRCA2) mutations with poor clinical outcomes in prostate cancer (PCa), but the impact of concurrent somatic events on gBRCA2 carriers survival and disease progression is unknown. PATIENTS AND METHODS: To ascertain the role of frequent somatic genomic alterations and histology subtypes in the outcomes of gBRCA2 mutation carriers and non-carriers, we correlated the tumour characteristics and clinical outcomes of 73 gBRCA2 and 127 non-carriers. Fluorescent in-situ hybridisation and next-generation sequencing were used to detect copy number variations in BRCA2, RB1, MYC and PTEN. Presence of intraductal and cribriform subtypes was also assessed. The independent impact of these events on cause-specific survival (CSS), metastasis-free survival and time to castration-resistant disease was assessed using cox-regression models. RESULTS: Somatic BRCA2-RB1 co-deletion (41% versus 12%, p < 0.001) and MYC amplification (53.4% versus 18.8%, p < 0.001) were enriched in gBRCA2 compared to sporadic tumours. Median CSS from diagnosis of PCa was 9.1 versus 17.6 years in gBRCA2 carriers and non-carriers, respectively (HR 2.12; p = 0.002), Median CSS in gBRCA2 carriers increased to 11.3 and 13.4 years in the absence of BRCA2-RB1 deletion or MYC amplification, respectively. Median CSS of non-carriers decreased to 8 and 2.6 years if BRCA2-RB1 deletion or MYC amplification were detected. CONCLUSIONS: gBRCA2-related prostate tumours are enriched for aggressive genomic features, such as BRCA2-RB1 co-deletion and MYC amplification. The presence or absence of these events modify the outcomes of gBRCA2 carriers.