Background:Abemaciclib is a selective cyclin-dependent kinase 4 and 6 inhibitor that penetrates the blood-brain barrier, resulting in comparable concentrations in tissue and plasma. The primary objective of this nonrandomized Simon two-stage phase II trial (NCT02308020) was to evaluate the intracranial objective response rate in patients with brain metastases secondary to breast cancer (already published), non-small cell lung cancer (NSCLC), or -melanoma receiving abemaciclib. Secondary objectives evaluated safety, extracranial response, progression-free survival (PFS), and overall survival (OS). Methods:Eligible subjects were enrolled in NSCLC or melanoma tumor-specific cohorts and treated with abemaciclib 200 mg twice daily (BID) monotherapy or 150 mg BID for NSCLC patients on concurrent pemetrexed or gemcitabine. Results:A total of 51 patients were enrolled (NSCLC, n = 28; melanoma, n = 23). No confirmed intracranial response was observed in either cohort. Volumetric decrease in target intracranial lesions was 22.7% for NSCLC and 18.8% for melanoma cohorts. Intracranial clinical benefit rate was 26.1% (95% CI: 8.1-44) for NSCLC and 9.1% (95% CI: 0-21.1) for melanoma cohorts. In the NSCLC cohort, median OS and PFS were 7.1 months (95% CI: 3.7-9.4) and 1.6 months (95% CI: 1.4-3.5), respectively. In the melanoma cohort, median OS and PFS were 2.9 months (95% CI: 1.2-4.3) and 1.4 months (95% CI: 1.0-2.0), respectively. Abemaciclib safety was consistent with previously reported data. Conclusions:Although abemaciclib can achieve therapeutic concentrations in brain metastases tissue, this study did not meet its primary endpoint. The limited clinical activity in this study suggests that further clinical trials should focus on the use of abemaciclib combination therapy.

Supplementary Figure S3. Figure showing overall survival in liquid only group.

Supplementary Table S2. Matching between genomic alteration and drug proposed by MTB in ITT population.

Supplementary Figure S1. Figure showing overall survival in the tissue only group.

PURPOSE:This analysis evaluated the influence of tissue and liquid biopsy concordance on outcomes in patients enrolled in the ROME trial. PATIENTS AND METHODS:The ROME trial, a phase II multicenter study, enrolled 1,794 patients with advanced solid tumors. Next-generation sequencing was performed on tissue and liquid biopsies using FoundationOne CDx and FoundationOne Liquid CDx. A centralized molecular tumor board reviewed results to identify actionable alterations, with 400 patients randomly assigned to tailored therapy (TT) or standard-of-care groups. TT improved objective response rate and progression-free survival (PFS) in the intention-to-treat population. Concordance was defined as the detection of the same druggable alteration in both biopsy types; discordance indicated detection in only one. RESULTS:Concordance was present in 49% of cases, with alterations detected exclusively in tissue (35%) or liquid (16%) biopsies. Patients in the concordant group receiving TT experienced improved survival outcomes. The median overall survival was 11.05 versus 7.70 months in the standard-of-care group [HR = 0.74; 95% confidence interval, 0.51-1.07], and the median PFS was 4.93 versus 2.80 months (HR = 0.55; 95% confidence interval, 0.40-0.76), respectively. In contrast, the survival benefit of TT was less pronounced or absent in patients with discordant results. Overall survival was higher in the T + L group (11.05 months), followed by tissue-only (9.93 months) and liquid-only (4.05 months) groups. PFS followed a similar pattern, with the longest PFS in the T + L group (4.93 months) versus 3.06 months in tissue-only and 2.07 months in liquid-only groups. CONCLUSIONS:The study highlights the potential value of integrating both biopsy modalities in selected clinical contexts. See related commentary by Saldanha and Siu, p. 7.

Supplementary Figure S2. Figure showing progression-free survival in the tissue only group.

PURPOSE:We aimed to investigate the prognostic and predictive value of tumor infiltrating lymphocytes (TILs) for adjuvant immunotherapy in high-risk early TNBC. PATIENTS AND METHODS:The phase III A-BRAVE trial randomized 466 patients with high-risk early TNBC to adjuvant avelumab or observation after standard therapy. Inclusion criteria allowed two strata: Stratum A (primary surgery followed by adjuvant chemotherapy, defined at high risk based on pathological stage) and Stratum B (neoadjuvant chemotherapy followed by surgery without pathological complete response). TILs were centrally assessed on treatment-naive tumor samples (BSL-TILs) and on residual disease after neoadjuvant chemotherapy (RD-TILs, Stratum B). Residual cancer burden (RCB) was assessed in Stratum B. Survival endpoints were: disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS). RESULTS:BSL-TILs were available for 387 patients, RD-TILs for 330 patients (290 with both BSL-TILs and RD-TILs). Higher BSL-TILs were independently associated with improved outcomes across all endpoints. In Stratum B, higher RD-TILs showed a significant independent association with improved outcomes, outperforming BSL-TILs. RCB was also independently prognostic. Avelumab improved outcomes only for patients with BSL-TILs ≥30%, particularly in Stratum B (3-yr DDFS rates 92.0% vs 58.7%, HR 0.20 in high BSL-TILs and 70.4% vs 70.1%, HR 0.92 in low BSL-TILs, interaction p=0.019). Similar results for DFS and OS. RCB was not predictive for avelumab benefit. CONCLUSIONS:TILs may predict benefit from adjuvant immunotherapy in early TNBC. These findings warrant validation and support TILs-guided immunotherapy strategies in future trials. TRIAL REGISTRATION:NCT02926196.

Supplementary Figure S9. Differences in variant coverage between tissue and liquid tests (Venn diagram).

1010 Background: Circadian rhythms regulate immune functions, and morning (AM) administration of immunotherapy (IO) is associated with survival in several solid tumors. However, whether time-of-day (ToDa) of IO delivery influences outcomes in early-stage triple-negative breast cancer (TNBC), and whether this effect depends on immune biomarkers, remains unknown. Methods: A-BRAVE randomized patients with high-risk early-stage TNBC to 1 year of adjuvant avelumab or observation. Infusion time of avelumab was retrieved from eCRF. AM-rate was calculated for each patient as the proportion of the first 4 infusions occurring before 12:30 PM (cohort median ToDa) and patients categorized as AM-dominant (AM-rate ≥50%) or PM-dominant. Tumor-infiltrating lymphocytes (TILs) and PD-L1 (Dako 73-10) were centrally assessed on treatment-naive tumor samples. We analyzed distant disease-free survival (DDFS) and overall survival (OS) by adjusted Cox models. Results: ToDa data were available for 221 avelumab-treated patients (94.0%); TILs and PD-L1 were evaluable in 188 (85%) and 195 (88%) of these, respectively. AM-rate was not associated with outcomes. However, ToDa effects were strongly immune-dependent. Increasing AM-rate was associated with improved DDFS and OS in immune-hot tumors (TILs [≥20%] or PD-L1 [≥21] high), but with worse outcomes in immune-cold tumors (TILs or PD-L1 low) (AM-rate*TILs interaction: DDFS p=0.008, OS p=0.001; AM-rate*PD-L1 interaction: DDFS p=0.030, OS p=0.039). These findings were concordant using AM-dominant vs. PM-dominant categorization (Table). Patients receiving immune-aligned treatment (immune-hot/AM-dominant OR immune-cold/PM-dominant) had superior survival compared with immune-misaligned (immune-hot/PM-dominant OR immune-cold/AM-dominant) and the observational arm (TILs-based: 3-year OS 95.7% vs 75.2% vs 78.0%; p<0.001; PD-L1-based: 3-year OS 93.4% vs 79.4% vs 76.1; p=0.035). Conclusions: In early-stage TNBC, time of IO administration may be a driver of efficacy, with opposing effects according to baseline immune milieu. Immune-informed circadian alignment may represent a previously unrecognized determinant of IO efficacy in TNBC. Clinical trial information: NCT02926196 . Outcome AM-dominant3-yr Rate % (95% CI) PM-dominant3-yr Rate % (95% CI) Log-rank p AM vs PM dominant HR (95% CI) TILs High DDFS 90.1 (81.3–99.8) 72.0 (56.4–91.9) 0.064 0.39 (0.13–1.21) OS 97.5 (92.8–100) 76.0 (61.0–94.7) 0.019 0.35 (0.10–1.20) TILs Low DDFS 63.1 (52.6–75.7) 84.7 (75.5–95.1) 0.003 2.61 (1.23–5.55) OS 74.9 (65.2–86.0) 94.3 (88.3–100) 0.003 3.84 (1.30–11.29) PD-L1 high DDFS 100 (100–100) 61.5 (40.0–94.6) 0.015 0.11 (0.01–0.94) OS 100 (100–100) 76.9 (57.1–100) 0.008 0.11 (0.01–1.03) PD-L1 low DDFS 66.4 (57.3–77.0) 83.0 (74.7–92.2) 0.026 1.82 (1.00–3.31) OS 79.8 (71.9–88.6) 91.5 (85.3–98.2) 0.025 2.05 (0.95–4.43)

Supplementary Figure S6. Figure showing progression-free survival in the discordant group.

Supplementary Table S1. Representativeness of Study Participants.

BackgroundCutaneous malignant melanoma represents a notable public health issue, characterized by a rapidly increasing incidence, particularly among younger populations. Despite progress in early detection and treatment modalities, this rising trend exacerbates the healthcare system’s burden. Limited research has been conducted on the impact of comorbidities on overall and melanoma-specific healthcare costs incurred by patients with melanoma. The objective of this study is to assess how various comorbidity patterns influence healthcare costs in this patient population.MethodsThis retrospective cohort study reviewed data from the Regional Cancer Registry of the Veneto Region (RTV) for melanoma diagnoses in 2019 and 2021. Patients were grouped into specific comorbidity clusters using latent class analysis, and the effect of these patterns on melanoma healthcare costs was evaluated from a health system perspective, considering only the direct costs incurred by the regional health care service.ResultsThe study included 2,978 cases of incident melanoma. The 2,114 patients with comorbidity data available were categorized into three comorbidity clusters: Circulatory-Metabolic-Respiratory, Psychosocial-Pregnancy related, and Multiorgan-Trauma. The mean unadjusted overall and melanoma-specific cumulative expenditure per patient increased with the number of comorbidities: melanoma-specific healthcare resources were € 13,537 (no comorbidity), € 16,828 (one comorbidity), € 20,396 (Multiorgan-Trauma cluster). Hospitalizations were the primary driver of cost escalation, particularly for patients with Multiorgan-Trauma comorbidities.ConclusionComorbidity patterns significantly impact melanoma management and related healthcare costs. Understanding these patterns can help optimize resource allocation and improve patient management strategies.

Background: The A-BRAVE trial showed an improvement in long-term outcome with the anti-PD-L1 avelumab administered as adjuvant therapy for high-risk early TNBC patients. Here, we report the efficacy of avelumab according to PD-L1, tumor infiltrating lymphocytes (TILs), and residual cancer burden (RCB). Methods: The phase III A-BRAVE trial randomized 466 patients with high risk early TNBC to 1-year avelumab vs observation after completion of standard surgery and neoadjuvant/adjuvant chemotherapy. High risk was defined as high disease burden in case of primary surgery (n=83 Stratum A) or invasive residual disease (breast and/or nodes) after neoadjuvant chemotherapy (n=383 Stratum B). Avelumab vs observation improved outcomes (Conte P ASCO 2024): +5.1% in 3-yr DFS in ITT and Stratum B (non-significant, co-primary endpoints); +8.5% in 3-yr OS in ITT (p=0.035) and Stratum B (p=0.070); +7.5% in 3-yr DDFS in ITT (p=0.028). Here, we report DFS (secondary endpoint), DDFS and OS by PD-L1 status in ITT, as well as DFS, DDFS and OS by post-neoadjuvant chemotherapy TILs and RCB in Stratum B. PD-L1 was evaluated on surgical tumor samples (Stratum A) and diagnostic core-biopsies (Stratum B) with the IHC 73-10 RUO assay (Agilent Technologies); the % of positive stromal cells/total stromal cells was calculated with digital pathology. PD-L1 high was defined according to a previously published >21% cut-off (Dieci MV, Eur J Cancer 2020). In Stratum B, surgical samples were evaluated for TILs (centrally) and RCB (locally) according to guidelines. Only p values <0.05 are shown. Results: PD-L1 expression was prognostic: every 1% increment was associated with improved DFS (HR 0.99, 95%CI 0.97-1.00, p=0.014), DDFS (HR 0.98, 95%CI 0.97-0.99, p=0.005) and OS (HR 0.99, 95%CI 0.97-1.00, p=0.049). PD-L1 high vs PD-L1 low patients showed better outcome: 3-yr DFS 80.6% vs 64.3%, p=0.004; 3-yr DDFS 85.1% vs 69.8%, p=0.002; 3-yr OS 89.6% vs 79.5%, p=0.032. No significant interaction between PD-L1 and treatment arm was observed for any efficacy endpoint. However, the benefit of avelumab vs control was more evident for PD-L1 low: 3-yr DFS 67.3% vs 61.1%, 3-yr DDFS 73.6% vs 65.9%, 3-yr OS 84.6% vs 74.1% in PD-L1 low; 3-yr DFS 77.1% vs 84.4%, 3-yr DDFS 85.7% vs 84.4%, 3-yr OS 91.4% vs 87.5% in PD-L1 high. In Stratum B, RCB was prognostic. Outcomes by RCB I, II and III were: 3-yr DFS 76.7%, 67.5%, 32.4%; 3-yr DDFS 76.5%, 73.6%, 39.7%; 3-yr OS 83.1%, 81.7%, 46.6%, p<0.001 for all endpoints. No significant interaction for any efficacy endpoint was observed between RCB and treatment arm. The benefit of avelumab vs control by RCB category was: RCB I (n=30, 3-yr DFS 84.6% vs 70.6%; 3-yr DDFS 84.6% vs 70.6%; 3-yr OS 84.6% vs 82.4%), RCB II (n=224, 3-yr DFS 67.3% vs 67.6%; 3-yr DDFS 75.8% vs 71.3%; 3-yr OS 87.4% vs 75.7%), RCB III (n=55, 3-yr DFS 44.6% vs 19.2%, p=0.028; 3-yr DDFS 55.0% vs 23.1%, p=0.003; 3-yr OS 57.5% vs 33.6%, p=0.026). TILs on residual disease were significantly prognostic in Stratum B: every 1% increase was associated with: HR 0.98 95%CI 0.97-0.99, p=0.002 for DFS; HR 0.98 95%CI 0.97-0.99, p=0.004 for DDFS; HR 0.98, 95%CI 0.96-1.00, p=0.010 for OS. Results were similar after correction for RCB. There was no significant interaction for any efficacy endpoint between TILs and treatment arm. The benefit of avelumab vs control was more evident in TILs<10% (3-yr DFS 57.7% vs 50.0%; 3-yr DDFS 64.7% vs 53.6%; 3-yr OS 74.6% vs 61.8%) than TILs>10% (3-yr DFS 72.5% vs 75.4%; 3-yr DDFS 81.5% vs 79.2%; 3-yr OS 89.6% vs 85.6%). Conclusions: Efficacy of avelumab for high-risk TNBC did not significantly differ by PD-L1 in the ITT, or by TILs and RCB in Stratum B. However, these biomarkers help identifying subgroups of patients at poorer prognosis deriving the greatest magnitude of benefit from this treatment. Citation Format: Maria Vittoria Dieci, Giancarlo Bisagni, Lorenzo Nicolé, Peter Schmid, Vittoria Fotia, Federico Piacentini, Adolfo Favaretto, Giulia Bianchi, Saverio Cinieri, Lucia Del Mastro, Domenico Corsi, Michelino de Laurentiis, Grazia Arpino, Marta Mion, Antonino Musolino, Antonella Ferro, Donata Sartori, Fable Zustovich, Simon Spazzapan, Alessandra Gennari, Claudio Zamagni, Stefano Tamberi, Tommaso Giarratano, Elisa Gasparini, Giovanna Magni, Gian Luca De Salvo, Pierfranco Conte, Valentina Guarneri. Efficacy of adjuvant avelumab by PD-L1, tumor infiltrating lymphocytes and residual cancer burden in high-risk triple negative breast cancer: secondary and exploratory endpoints of the phase III A-BRAVE trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr RF3-02.

The increasing incidence of cutaneous melanoma (CM) is a significant public health issue. However, few studies have focused on how comorbidity patterns may influence the outcomes of CM patients. This study aimed to identify comorbidity patterns among CM patients and assess their impact on survival rates. This retrospective population-based cohort study included all CM patients recorded in the regional Veneto Cancer Registry in 2019 and 2021. Comorbidity data (ICD-9-CM coding) were obtained from hospital discharge records and included 17 primary disease categories. Patients with at least two documented conditions were clustered via latent class analysis (LCA), with the optimal number of clusters determined via the Akaike information criterion (AIC). This population-based retrospective cohort study included 2,114 CM patients. Coexisting medical conditions were documented in 1,048 (49.6

Importance For patients with early ERBB2 (formerly HER2 )–positive breast cancer, there is a need to identify biomarkers to guide treatment de-escalation. Objective To evaluate the association of tumor-infiltrating lymphocytes (TILs) with distant disease-free (DDFS) and overall survival (OS) for patients with ERBB2 -positive early breast cancer. Design, Setting, and Participants The ShortHER randomized clinical trial was a multicentric trial in Italy that enrolled patients with ERBB2 -positive breast cancer from December 2007 to October 2013. Patients received 9 weeks or 1 year of adjuvant trastuzumab combined with chemotherapy. Tumor samples were evaluated for TILs. Herein, patients were evaluated at a median follow-up of 9 years, and data were analyzed from February 2023 to August 2024. Intervention Four cycles of anthracycline-based chemotherapy followed by 4 courses of taxanes combined with trastuzumab for 1 year (long arm) or 3 courses of taxanes combined with trastuzumab for 9 weeks followed by reduced-dose anthracycline-based chemotherapy for 3 courses (short arm). Main Outcomes and Measures The association of TILs with DDFS and OS was assessed with Cox models. Results Of 1253 patients enrolled in the ShortHER trial, 866 women (median [IQR] age, 56 [48-64] years) had evaluable TILs. In Cox models with relevant factors, each 5% TIL increment was associated with improved DDFS (hazard ratio [HR], 0.87; 95% CI, 0.80-0.95; P = .001) and OS (HR, 0.89; 95% CI, 0.81-0.98; P = .01). The 10-year OS rate was 91.3% for patients with TILs 20% or higher, 93.3% for patients with TILs 30% or higher, and 98.1% for patients with TILs 50% or higher, resulting higher vs lower TIL counterparts. Patients with TILs lower than 20% showed a better outcome with the long vs short treatment (10-year DDFS, 88.7% vs 81.0%), whereas patients with TILs 20% or higher showed the opposite (10-year DDFS, 87.1% vs 92.2%; P for interaction = .01). Similarly, patients with TILs 20% or higher had a 10-year OS rate of 89.3% in the long arm vs 93.1% in the short arm (HR, 0.36; 95% CI, 0.10-1.36); patients with TILs lower than 20% had a 10-year OS rate of 91.3% in the long arm vs 86.9% in the short arm (HR, 1.36; 95% CI, 0.82-2.23; P for interaction = .06). Conclusions and Relevance This follow-up analysis of the ShortHER randomized clinical trial is, to our knowledge, the first demonstration of an independent effect of TILs in terms of OS for patients with ERBB2 -positive early breast cancer treated with adjuvant chemotherapy and anti- ERBB2 therapy. Patients with TILs 20% or higher who de-escalated trastuzumab duration and chemotherapy dose were not exposed to an excess risk of distant relapse or death. Trial Registration EudraCT: 2007-004326-25

Introduction: This retrospective follow-up study evaluates patient outcomes and treatment costs in two cohorts of incident NSCLC patients recorded in the population-based cancer registry of the Veneto Region in 2017 and 2019. Methods: This study examines two cohorts of incident NSCLC patients recorded by the Regional Veneto cancer registry in 2017 (493 patients) and 2019 (557 patients). Cancer patients were followed for three years after diagnosis to assess the disease's outcomes and analyze the overall treatment-related costs. Overall survival and cancer-specific mortality were evaluated using Cox regression models. The log-transformed overall treatment costs for the 3 years following diagnosis were analyzed using linear regression. Results: The overall mortality risk significantly lowered in the 2019 cohort (HR 0.84; 95% CI 0.72-0.98, p = 0.024). Stage III patients were not associated with a significant overall survival rate (HR 0.71; 95% CI 0.50-1.02; p = 0.065) but were associated with significantly higher cancer-specific survival (HR 0.61; 95% CI 0.41-0.91; p = 0.015). Overall, the 2019 cohort showed significantly higher costs (coefficient 0.16; 95% CI 0.02-0.30, p = 0.025), particularly as a result of increases in the costs of drug administration, outpatient services, and medical devices. However, during the same 3-year follow-up period, this cohort featured lower average costs for hospice care and hospitalizations. Conclusions: These results revealed notable differences in clinical outcomes and patient-related costs in incident NSCLCs in 2017 and 2019. The study highlights the importance of monitoring clinical outcomes and management costs in real-world oncology practice.

Adjuvant trastuzumab in combination with chemotherapy has significantly improved survival in patients with HER2-positive early breast cancer but, since introduction in 2005, the 12 months duration has been questioned and trials have tested shorter durations. A systematic review and meta-analysis using individual patient data (IPD) (when available) from non-inferiority trials of reduced duration trastuzumab was carried out according to PRISMA-IPD guidelines. Primary outcome was invasive disease-free survival (IDFS); secondary outcomes were distant relapse-free survival (DRFS) and overall survival (OS). Estimated survival was calculated using random-effects and fixed-effects modelling, reported by 5 year rates and analysed using non-inferiority methods. Illustrative comparative risks were also tabled as in Cochrane Systematic Reviews. Five trials were identified: PERSEPHONE, PHARE and HORG compared 12 months (m) with 6 m; SOLD and Short-HER compared 12 m with 9 weeks. In the 5-trial analysis (11 389 patients), and in the SOLD and Short-HER (3428 patients) analysis, non-inferiority of the shorter duration was not confirmed. In contrast, for the comparison of 12 m versus 6 m (7961 patients), non-inferiority was confirmed with a 2.5% critical margin, for IDFS, DRFS and OS. The Kaplan-Meier curves demonstrated overlap of credibility intervals throughout follow-up. For every 1000 patients given 6 m trastuzumab, by 5 years, there might be 11 extra IDFS events (in addition to 141 expected for 12 m), 12 more DRFS events (in addition to 106) and nine more deaths (in addition to 73). We have demonstrated that 6 m trastuzumab in early HER2-positive breast cancer is not inferior to 12 m and is an option for patients. CRD42020172267.

Introduction: Comorbidities affect diagnosis and treatments in cancer patients. This study explores the prevalence and patterns of comorbidities in non-small cell lung cancer (NSCLC) patients and their association with survival. Materials and Methods: This retrospective population-based cohort study included 1674 incident NSCLC patients. Comorbidities were classified based on the ICD-9-CM system, with 13 disease categories analyzed. Patients with more than two comorbidities were classified into three mutually exclusive and exhaustive latent classes (Latent Class Analysis [LCA]). The optimal number of latent classes was determined by applying the Akaike Information Criterion. Cox regression models were run to assess overall and cancer-specific mortality, adjusting for the comorbidity groups, sex, age, and stage at diagnosis. Results: In 1674 NSCLC patients, the most prevalent medical conditions were respiratory (35.8%) and cardiovascular (33.5%). The Cox regression showed that even one comorbidity is associated with an increased hazard of overall mortality (HR = 1.33, 95%CI: 1.11–1.59, p = 0.002). LCA-derived Class-1 (cardiovascular-respiratory and endocrine) reported HR = 1.74 (95%CI: 1.39–2.17, p < 0.001), Class-2 (multi-organ) HR = 1.44 (95%CI: 1.18–1.77, p < 0.001), and Class-3 (socio-multifactorial-neuro) HR = 1.62 (95%CI: 1.36–1.93, p < 0.001). Instead, in patients with one comorbidity, NSCLC-specific mortality showed no significant trend towards increased risk (HR = 1.17, 95%CI: 1.00–1.43, p = 0.114). Significant associations emerged between NSCLC-specific mortality and LCA-classes: Class-1: HR = 1.49 (95%CI: 1.20–1.91, p = 0.001); Class-2 HR = 1.25 (95%CI: 1.0–1.57 p = 0.048); and Class-3: HR = 1.23 (95%CI: 1.00–1.48, p = 0.035). Conclusions: The adverse impact of comorbidities on NSCLC-specific mortality requires their inclusion as risk factors in cancer treatment and prognosis.