Premature mortality trends in 183 countries by cancer type, sex, WHO region, and World Bank income level in 2000-19: a retrospective, cross-sectional, population-based study.

BACKGROUND: Cancer is a leading cause of mortality worldwide. By 2040, over 30 million new cancers are predicted, with the greatest cancer burden in low-income countries. In 2015, the UN passed the Sustainable Development Goal 3.4 (SDG 3.4) to tackle the rising burden of non-communicable diseases, which calls for a reduction by a third in premature mortality from non-communicable diseases, including cancer, by 2030. However, there is a paucity of data on premature mortality rates by cancer type. In this study, we examine annual rates of change for cancer-specific premature mortality and classify whether countries are on track to reach SDG 3.4 targets. METHODS: This is a retrospective, cross-sectional, population-based study investigating premature mortality trends from 2000-19 using the WHO Global Health Estimates data. All cancers combined and thirteen individual cancers in 183 countries were examined by WHO region, World Bank income level, and sex. The risk of premature mortality was calculated for ages 30-69 years, independent of other competing causes of death, using standard life table methods. The primary objective was to compute average annual rate of change in premature mortality from 2000 to 2019. Secondary objectives assessed whether this annual rate of change would be sufficient to reach SDG 3.4. targets for premature mortality by 2030. FINDINGS: This study was conducted using data retrieved for the years 2000-19. Premature mortality rates decreased in 138 (75%) of 183 countries across all World Bank income levels and WHO regions, however only eight (4%) countries are likely to meet the SDG 3.4 targets for all cancers combined. Cancers where early detection strategies exist, such as breast and colorectal cancer, have higher declining premature mortality rates in high-income countries (breast cancer 48 [89%] of 54 and colorectal cancer 45 [83%]) than in low-income countries (seven [24%] of 29 and four [14%]). Cancers with primary prevention programmes, such as cervical cancer, have more countries with declining premature mortality rates (high-income countries 50 [93%] of 54 and low-income countries 26 [90%] of 29). Sex-related disparities in premature mortality rates vary across WHO regions, World Bank income groups, and by cancer type. INTERPRETATION: There is a greater reduction in premature mortality for all cancers combined and for individual cancer types in high-income countries compared with lower-middle-income and low-income countries. However, most countries will not reach the SDG 3.4 target. Cancers with early detection strategies in place, such as breast and colorectal cancers, are performing poorly in premature mortality compared with cancers with primary prevention measures, such as cervical cancer. Investments toward prevention, early detection, and treatment can potentially accelerate declines in premature mortality. FUNDING: WHO.

Association of opioid use with survival in patients with cancer treated with immune checkpoint inhibitors: it is time for evidence-based behaviors.

Cancer is a leading cause of morbidity and mortality worldwide, with pain experienced by most patients undergoing cancer treatment. Opioids are the recommended treatment for cancer pain management, but recent studies suggest a negative association between opioid use and survival rates among patients undergoing immunotherapy. However, conclusions cannot be drawn regarding causality from these observational data. Immunotherapy, which boosts the body's immune system to fight cancer cells, has emerged as a promising treatment option for all types of cancer. Immune checkpoint inhibitors (ICIs) can activate the anticancer function of exhausted T cells and have shown remarkable survival benefits in patients with multiple malignancies. However, a recent systematic review and meta-analysis suggested that the use of opioids during ICI treatment has an adverse effect on patient prognosis, while the use of NSAIDs is not significantly associated with the prognosis in patients treated with ICIs. These reviews have major limitations due to the retrospective nature of the studies and the multiple factors that can influence the phenomenon. Therefore, caution is required when interpreting results from retrospective data on drug interactions. The findings of this study are alarming and potentially harmful to patients with cancer suffering from pain or other symptoms requiring opioid drugs.

Baseline Tumor Size as Prognostic Index in Patients With Advanced Solid Tumors Receiving Experimental Targeted Agents.

BACKGROUND: Baseline tumor size (BTS) has been associated with outcomes in patients with cancer treated with immunotherapy. However, the prognostic impact of BTS on patients receiving targeted therapies (TTs) remains undetermined. METHODS: We reviewed data of patients with advanced solid tumors consecutively treated within early-phase clinical trials at our institution from 01/2014 to 04/2021. Treatments were categorized as immunotherapy-based or TT-based (biomarker-matched or not). BTS was calculated as the sum of RECIST1.1 baseline target lesions. RESULTS: A total of 444 patients were eligible; the median BTS was 69 mm (IQR 40-100). OS was significantly longer for patients with BTS lower versus higher than the median (16.6 vs. 8.2 months, P < .001), including among those receiving immunotherapy (12 vs. 7.5 months, P = .005). Among patients receiving TT, lower BTS was associated with longer PFS (4.7 vs. 3.1 months, P = .002) and OS (20.5 vs. 9.9 months, P < .001) as compared to high BTS. However, such association was only significant among patients receiving biomarker-matched TT, with longer PFS (6.2 vs. 3.3 months, P < .001) and OS (21.2 vs. 6.7 months, P < .001) in the low-BTS subgroup, despite a similar ORR (28% vs. 22%, P = .57). BTS was not prognostic among patients receiving unmatched TT, with similar PFS (3.7 vs. 4.4 months, P = .30), OS (19.3 vs. 11.8 months, P = .20), and ORR (33% vs. 28%, P = .78) in the 2 BTS groups. Multivariate analysis confirmed that BTS was independently associated with PFS (P = .03) and OS (P < .001) but not with ORR (P = .11). CONCLUSIONS: Higher BTS is associated with worse survival outcomes among patients receiving biomarker-matched, but not biomarker-unmatched TT.

PARP inhibitor resistant BRCA-mutated advanced breast cancer: current landscape and emerging treatments.

PURPOSE OF REVIEW: Patients with advanced breast cancer (aBC) treated with PARP inhibitors (PARPi) can eventually experience disease progression for emerging treatment resistance. This review aims to depict the treatment the molecular landscape, and the innovative therapies for patients with PARPi-resistant BRCA-mutated aBC. RECENT FINDINGS: No specific therapy is specifically available in the setting post-PARPi-failure, with antibody-drug conjugates or nonplatinum-based chemotherapy (PBC) representing the best treatment options in this setting. Mechanisms of on-target PARPi resistance can be classified in reversions (60%) and nonreversion (40%); reverse mutations restore PARP functions. According to the first evidence of clinical validity, these alterations are associated with lower efficacy of PARPi and PBC. However, their clinical utility needs to be assessed. SUMMARY: PARPi-resistant aBC represents a clinical unmet need due to the lack of specific targeted therapies and validated prognostic and predictive biomarkers. Constant efforts are required to better define the mechanisms of PARPi resistance and, consequently, develop biomarker-based treatment approach to prevent or overcame resistance.

Antibody-drug conjugates in metastatic breast cancer: sequencing, combinations and resistances.

PURPOSE OF REVIEW: Significant advancements have been made in treating metastatic breast cancer (MBC) with antibody drug conjugates (ADCs). However, due to the development of resistance, patients experience disease progression. The aim of this review is to summarize current evidence on ADCs sequencing strategies and combination approaches in the treatment of MBC. RECENT FINDINGS: Concerning HER2 positive MBC, current evidence on the optimal ADC-sequencing is primarily about T-DXd, which demonstrated therapeutic value when used post-T-DM1. Conversely, data are limited about the reverse sequence. Similarly, in HER2-negative MBC, recent studies evaluated the sequential use of Sacituzumab Govitecan and T-DXd, which was associated with poor responses. Retrospective analyses have not demonstrated an optimal sequencing strategy for ADCs, and it is still very unclear whether switching the payload or targeting a different antigen may represent the best approach. Combinations may better overcome ADC resistance: interesting data associating immunotherapy or tyrosine kinase inhibitors to ADCs appear promising, albeit data are still immature. SUMMARY: In MBC, ADCs have expanded treatment options but their sequential use requires further study. Evidence suggests that sequencing ADCs with similar payloads is ineffective, though current data are inconclusive. More research is needed to optimize treatment strategies, including potential combination therapies.

Genomic tests for risk stratification in patients with early human epidermal growth factor receptor 2-positive breast cancer.

PURPOSE OF REVIEW: The purpose of this review is to provide a comprehensive overview of human epidermal growth factor receptor 2 (HER2) genomic tests, particularly focusing on the most recent developments and looking at the future prospects of this field, yet to be thoroughly explored. RECENT FINDINGS: HER2DX is a multifeatured assay, retrospectively proved to add prognostic information and to predict pathological complete response (pCR) in patients with HER2-positive early breast cancer (EBC) undergoing neoadjuvant treatment containing HER2-directed agents. Preliminary data have shown that the assay maintains its predictive capabilities even in the context of chemotherapy-free, anti-HER2 neoadjuvant regimens, potentially selecting patients suitable for treatment de-escalation, having highly HER2-driven malignancies. SUMMARY: Multigene prognostic assays have become essential tools in the management of EBC, providing crucial information for risk stratification.

Surgical and Oncological Outcomes of Level III-IV Versus Level I-II Inferior Vena Cava Thrombectomy: A Decennial Experience of a High-Volume European Referral Center.

BACKGROUND: In patients with renal cell carcinoma (RCC) the role of the extent of tumor thrombus into the inferior vena cava (IVC) has never been addressed from a surgical and oncologic standpoint. This study aims to evaluate differences between level III-IV versus level I-II patients concerning peri- and postoperative morbidity, additional treatments and long-term oncological outcomes. PATIENTS AND METHODS: Overall, 40 patients with RCC underwent radical nephrectomy (RN) with IVC thrombectomy at a single European institution between 2010 and 2023. Complications were reported according to the European Union (EAU) guidelines recommendations. Spider chart served as graphical depiction of surgical and oncologic outcomes. RESULTS: Overall, 22 (55%) and 18 (45%) patients harbored level III-IV and I-II IVC thrombus. Level III-IV patients experienced significantly higher rates of intraoperative transfusions (68 vs 39%), but not significantly higher rates of intraoperative complications (32% vs 28%). Level III-IV patients had significantly higher rates of postoperative transfusions (82% vs 33%) and Clavien Dindo ≥3 complications (41% vs 15%). In level III-IV versus level I-II patients, median follow up was 482 and 1070 days, the rate of distant recurrence was 59% and 50%, the rate of systemic progression was 27% and 13%, and the rate of additional treatment/s was 64% and 61%, respectively (all p values > 0.05). Overall survival was 36% in level III-IV patients and 67% in level I-II (p = 0.001). CONCLUSIONS: Our findings suggest that patients with level III-IV RCC who are candidates for IVC thrombectomy should be counselled about the higher likelihood of postoperative severe adverse events and worse overall survival relative to level I-II counterparts.

New horizons for platinum-resistant ovarian cancer: insights from the 2023 American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) Annual Meetings.

Platinum-resistant ovarian cancer is difficult to treat and has a poor prognosis. Patients with platinum-resistant ovarian cancer have limited treatment options and often have a limited benefit from existing chemotherapeutic agents. There is a lack of contemporary effective anticancer drugs and reliable predictive biomarkers for this aggressive cancer. Recent cutting-edge research presented at the 2023 American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) Annual Meetings has provided insights into several potential therapeutic targets, such as DNA damage repair proteins, cell-cycle regulators, and immune-modulating agents. In addition, antibody-drug conjugates have provided new practice-changing results in platinum-resistant ovarian cancer. Here, we review the results of research presented at this annual event, with a focus on clinical trials investigating novel treatment approaches for platinum-resistant ovarian cancer, in addition to predictive and prognostic biomarkers for optimal patient selection, and other topics, such as real-world evidence.

Health technology assessment for cancer medicines across the G7 countries and Oceania: an international, cross-sectional study.

BACKGROUND: Criticisms have emerged that cancer medicines offer modest benefits at increasingly high prices. Reimbursement decisions made by health technology assessment (HTA) agencies have become a complex endeavour for cancer medicines. Most high-income countries (HICs) use HTA criteria to identify high-value medicines for reimbursement under public drug coverage plans. We compared HTA criteria specific for cancer medicines in economically similar HICs, to understand how these criteria contribute to reimbursement decisions. METHODS: We did an international, cross-sectional analysis in collaboration with author investigators across eight HICs, from the Group of Seven (known as G7; Canada, England, France, Germany, Italy, and Japan) and Oceania (Australia and New Zealand). Publicly available data from HTA agency reports and official documentation were extracted and analysed between Aug 15, 2021, and July 31, 2022. We collected data pertaining to the decision-making criteria used by the national HTA agency; HTA reimbursement status for 34 medicine-indication pairs corresponding to 15 unique US top-selling cancer medicines; and HTA reimbursement status for 18 cancer medicine-indication pairs (13 unique medicines) with minimal clinical benefit (score of 1 on the European Society of Medical Oncology Magnitude of Clinical Benefit Scale). Descriptive statistics were used to compare HTA decision criteria and drug reimbursement recommendations (or for Germany and Japan, final reimbursement status) across the eight countries. FINDINGS: Therapeutic impact related to clinical outcomes of the new medicine was a uniform criterion across the eight countries, whereas quality of evidence (under the remit of therapeutic impact assessment) and equity were infrequently cited criteria. Only the German HTA agency mandated that surrogate endpoints be validated in therapeutic impact assessment. All countries except Germany included formal cost-effectiveness analyses within HTA reports. England and Japan were the only countries that specified a cost-effectiveness threshold. Of the 34 medicine-indication pairs corresponding to US top-selling cancer medicines, Germany reimbursed the maximum (34 [100%]), followed by Italy (32 [94%] recommended for reimbursement), Japan (28 [82%] reimbursed), Australia, Canada, England, and France (27 [79%] recommended for reimbursement), and New Zealand (12 [35%] recommended for reimbursement). Of the 18 cancer medicine-indication pairs with marginal clinical benefit, Germany reimbursed 15 (83%) and Japan reimbursed 12 (67%). France recommended nine (50%) for reimbursement, followed by Italy (seven [39%]), Canada (five [28%]), and Australia and England (three [17%] each). New Zealand did not recommend any medicine-indications with marginal clinical benefit for reimbursement. Considering the overall cumulative proportion across the eight countries, 58 (21%) of 272 indications for the US top-selling medicines and 90 (63%) of 144 marginally beneficial medicine-indications were not recommended for reimbursement or reimbursed. INTERPRETATION: Our findings indicate discordance in public reimbursement decisions across economically similar countries, despite overlapping HTA decision criteria. This suggests a need for improved transparency around the nuances of the criteria to ensure improved access to high-value cancer medicines, and deprioritisation of low-value cancer medicines. Health systems have opportunities to improve their HTA decision-making processes by learning from the systems in other countries. FUNDING: None.

Predicting Response to Antibody Drug Conjugates: A Focus on Antigens' Targetability.

Antibody-drug conjugates (ADCs) represent a cornerstone in the treatment of many cancers nowadays. ADCs fulfill their function by binding a target on tumor cell membrane to deliver a cytotoxic payload; in addition, those moieties capable of crossing cancer cell membranes can achieve near-by cells that do not express the target antigen, exerting the so-called "bystander" cytotoxic effect. The presence of a specific target antigen expressed on cancer cells has been for long considered crucial for ADCs and commonly required for the inclusion of patients in clinical trials with ADCs. To date, only ado-trastuzumab-emtansine, fam-trastuzumab deruxtecan-nxki, and mirvetuximab soravtansine-gynx are approved according to the expression of a target antigen in solid tumors, while the clinical use of other ADCs (eg, sacituzumab govitecan) is not conditioned by the presence of a specific biomarker. Given the ever-growing number of approved ADCs and those under investigation, it is essential to find new biomarkers to guide their use, especially in those settings for which different ADCs are approved to establish the best therapeutic sequence based on robust biomarkers. Hence, this work addresses the role of target antigens in predicting response to ADCs, focusing on examples of antigens' targetability according to their expression on cancer cells' surface or to the presence of specific target aberrations (eg, mutation or over-expression). New methods for the assessment and quantification of targets' expression, like molecular imaging and in vitro assays, might be key tools to improve biomarker analysis and eventually deliver better outcomes by refined patient selection.

Immunotherapy for inflammatory breast cancer: current evidences and future perspectives.

PURPOSE OF REVIEW: Inflammatory breast cancer (IBC) is the most fatal type presentation of clinical breast cancer. The immune tumor microenvironment (TME) of IBC is characterized by signals of immune evasion but suggests actionable vulnerability to immune-checkpoint inhibitors (ICIs). In this review, we aimed to summarize the most important preclinical evidences of IBC immune-vulnerability and the first data from clinical trials evaluating ICIs in IBC. RECENT FINDINGS: IBC is characterized by a preexisting active immune TME suppressed by mechanisms of immune-escape, including inhibitory immune-checkpoints, whose expression is higher than in non-IBC. Clinical trials evaluating ICIs in patients with IBC are burdened by slow accrual and low enrollment. SUMMARY: Because of the limited data from clinical trials, no conclusions about the activity of ICIs in IBC can be drawn. Ongoing clinical trials are assessing many promising ICI-based combination approaches. An enhanced multicenter collaboration to evaluate ICIs in patients with this aggressive form of disease and to improve clinical outcomes is required.

Mechanisms of Endocrine Resistance in Hormone Receptor-Positive Breast Cancer.

Hormone receptor-positive (HR+) breast cancer (BC) accounts for approximately 70% of all breast invasive tumors. Endocrine therapy (ET) represents the standard treatment for HR + BC. Most patients, however, eventually develop resistance to ET, which limits their effectiveness and poses a major challenge for the management of HR + BC. Several mechanisms that contribute to ET resistance have been described. One of the most common mechanisms is the upregulation of alternative signaling pathways that can bypass estrogen dependency, such as activation of the PI3K/Akt/mTOR as well as mitogen-activated protein kinase (MAPK) and the insulin-like growth factor 1 receptor (IGF-1R) pathways. Another common mechanism of endocrine resistance is the acquisition of activating mutations of ESR1, which encodes for the estrogen receptor, that lead to structural changes of the receptor, prevent the binding to anti-estrogen drugs and result in constitutive activation of the receptor, even in the absence of estrogens. Epigenetic changes, such as DNA methylation and histone modifications, can also contribute to ET resistance by altering the expression of genes that are involved in estrogen signaling. Understanding the mechanisms of resistance to ET is crucial for the development of new therapies that can overcome resistance and improve outcomes for patients with HR + BC.

Next-Generation Sequencing for Advanced Breast Cancer: What the Way to Go?

The rapid implementation of precision medicine tools in diagnosing and treating breast cancer (BC) has widened the potential therapeutic options for patients. The applications of gene sequencing, including next-generation gene sequencing (NGS), have led to numerous questions on how to validate, implement, interpret, prioritize and operationalize precision medicine tools to deliver meaningful and impactful interventions. Limited benefit has been portended with earlier experiences of NGS-driven treatment, in BC. However, the development and use of frameworks of clinical actionability of genomic alterations, for example, detected with NGS, has resulted in better patient selection, and potentially higher therapeutic value. The European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT) is a framework that includes five tiers of clinical actionability, with tier 1 reserved for approved drugs with demonstrated benefits for targetable genomic alterations. The re-analysis of clinical studies by grouping the genomic alterations and matched drugs with ESCAT, in high vs lower tiers has demonstrated a significant benefit portended by high tiers alterations, with the availability of efficacious treatments. As a result, frameworks for actionability, like ESCAT, should be fundamental in developing and implementing NGS-driven, and broadly, precision medicine research and treatments.

The Global Landscape on the Access to Cancer Medicines for Breast Cancer: The ONCOLLEGE Experience.

There is a growing global debate over barriers affecting the timely access to innovative anticancer therapies. Access to medicines is often traced back to the issue of costs: however, more commonly, the distance between valuable innovative treatments and the actual treatment of patients is far beyond the mere problem of financial barriers. A comprehensive approach to understand, assess to medicines should be pursued, to dissect the determinants and formulate solutions for all patients. In this chapter, we discuss drivers of access to innovation for patients with breast cancer, based on a case study of access to HER2-diagnositcs and therapeutics yielding a global landscape analysis, based on the efforts and expertise of the global collaborative group "ONCOLLEGE".

Screening Programs for Breast Cancer: Toward Individualized, Risk-Adapted Strategies of Early Detection.

Early detection of breast cancer (BC) comprises two approaches: screening of asymptomatic women in a specified target population at risk (usually a target age range for women at average risk), and early diagnosis for women with BC signs and symptoms. Screening for BC is a key health intervention for early detection. While population-based screening programs have been implemented for age-selected women, the pivotal clinical trials have not addressed the global utility nor the improvement of screening performance by utilizing more refined parameters for patient eligibility, such as individualized risk stratification. In addition, with the exception of the subset of women known to carry germline pathogenetic mutations in (high- or moderately-penetrant) cancer predisposition genes, such as BRCA1 and BRCA2, there has been less success in outreach and service provision for the unaffected relatives of women found to carry a high-risk mutation (i.e., "cascade testing") as it is in these individuals for whom such actionable information can result in cancers (and/or cancer deaths) being averted. Moreover, even in the absence of clinical cancer genetics services, as is the case for the immediate and at least near-term in most countries globally, the capacity to stratify the risk of an individual to develop BC has existed for many years, is available for free online at various sites/platforms, and is increasingly being validated for non-Caucasian populations. Ultimately, a precision approach to BC screening is largely missing. In the present chapter, we aim to address the concept of risk-adapted screening of BC, in multiple facets, and understand if there is a value in the implementation of adapted screening strategies in selected women, outside the established screening prescriptions, in the terms of age-range, screening modality and schedules of imaging.

Essential medicines list in national cancer control plans: a secondary analysis from a global study.

With the advent of innovative therapeutics for and the rising costs of cancer management, low-income and middle-income countries face increasing challenges to deliver effective and sustainable health care. Understanding of how countries are selecting and prioritising essential cancer interventions is poor, including in the formulation of policies for essential medicines. We did an in-depth subanalysis from a global dataset of national cancer control plans (NCCPs), aiming to identify possible determinants of inclusion of policies related to essential medicines in the NCCP. The results showed poor global comprehensiveness of NCCPs, and substantial deficits in policies for financial hardships due to cancer care, specifically for access to cancer medicines. Specification of budget allocations, policy of protection from catastrophic health expenditure, and national treatment guidelines in the NCCPs contributed to more consistent policies on essential cancer medicines. The bedrock to deliver effective cancer programmes resides in the assurance of comprehensive, consistent, and coherent policy formulation, to orient resource selection and health investments, ultimately delivering equitable health for all.

Circulating tumour DNA dynamics for assessment of molecular residual disease and for intercepting resistance in breast cancer.

PURPOSE OF REVIEW: Longitudinal evaluation of circulating tumour DNA (ctDNA) represents a promising tool for monitoring tumour evolution. In patients with breast cancer, ctDNA dynamics for the assessment of molecular residual disease (MRD) and resistances may, respectively, help clinicians in treatment modulation of adjuvant treatments, and in anticipating resistance to ongoing treatments and switch treatments before clinical progression, to improve disease control. Anyway, the introduction of this dynamic biomarker into clinical practice requires the demonstration of analytical validity, clinical validity and clinical utility. RECENT FINDINGS: In early breast cancer setting, several observational studies demonstrated the clinical validity of MRD monitoring through ctDNA in identifying patients at a higher risk of relapse, but many clinical trials evaluating the clinical utility are still ongoing, and few data resulted in inconclusive results.Instead, ctDNA dynamics for intercepting resistance have not been fully evaluated in terms of clinical validity, because monitoring schedules of most observational studies are not intensive. The only trial assessing their clinical utility (PADA-1) demonstrated a benefit in terms of progression-free survival, portraying a new landscape for clinical trials in this space. SUMMARY: Rigorous clinical trials with adequate assays and patient-relevant endpoints are paramount to demonstrate the clinical utility of ctDNA dynamics and eventually increase clinical outcomes.

Postneoadjuvant treatment for triple-negative breast cancer.

PURPOSE OF REVIEW: Triple-negative breast cancer (TNBC) has been conventionally associated with poor prognosis, as a result of limited therapeutic options. In the early setting, prognosis is informed by clinical-pathological factors; for patients receiving neoadjuvant treatments, pathological complete response (pCR) is the strongest factor. In this review, we mapped the landscape of clinical trials in the postneoadjuvant space, and identified three patterns of clinical trial design. RECENT FINDINGS: For patients at higher risk, effective postneoadjuvant treatments are of paramount importance to address a high clinical need. Postneoadjuvant risk-adapted treatments have demonstrated to improve survival in patients at high of recurrence. SUMMARY: Patients at high risk have indication for adjuvant treatment intensification, informed by baseline clinical, pathological or molecular factors (type 1 approach), on the presence, extent and molecular characteristics of the residual disease at the time of surgery (type 2) or on risk factors assessed in the postsurgical setting (type 3), for example, circulating tumour DNA. Most of the past trials were based on type 2 approaches, for example, with capecitabine and Olaparib. Few trials were based on a type 1 approach, notably pembrolizumab for early TNBC. The clinical validity of type 3 approaches is under investigation in several ongoing trials.

Challenging cases in high-risk prostate cancer patients treated with Retzius-sparing robot-assisted radical prostatectomy.

OBJECTIVE: To evaluate the relationship between enlarged prostate, bulky median lobe (BML) or prior benign prostatic hyperplasia (BPH) surgery and perioperative functional, and oncological outcomes in high-risk (HR) prostate cancer (PCa) patients treated with Retzius-sparing robot-assisted radical prostatectomy (RS-RARP). METHODS: 320 HR-PCa patients treated with RS-RARP between 2011 and 2020 at a single high-volume center. The relationship between prostate volume, BML, prior BPH surgery and perioperative outcomes, Clavien-Dindo (CD) grade ≥ 2 90-day postoperative complications, positive surgical margins (PSMs), and urinary continence (UC) recovery was evaluated respectively in multivariable linear, logistic and Cox regression models. Complications were collected according to the standardized methodology proposed by EAU guidelines. UC recovery was defined as the use of zero or one safety pad. RESULTS: Overall, 5.9% and 5.6% had respectively a BML or prior BPH surgery. Median PV was 45 g (range: 14-300). The rate of focal and non-focal PSMs was 8.4% and 17.8%. 53% and 10.9% patients had immediate UC recovery and CD ≥ 2. The 1- and 2-yr UC recovery was 84 and 85%. PV (p = 0.03) and prior BPH surgery (p = 0.02) was associated with longer operative time. BML was independent predictor of time to bladder catheter removal (p = 0.001). PV was independent predictor of PSMs (OR: 1.02; p = 0.009). Prior BPH surgery was associated with lower UC recovery (HR: 0.5; p = 0.03). CONCLUSION: HR-PCa patients with enlarged prostate have higher risk of PSMs, while patients with prior BPH surgery have suboptimal UC recovery. These findings should help physicians for accurate preoperative counseling and to improve surgical planning in case of HR-PCa patients with challenging features.

National health system characteristics, breast cancer stage at diagnosis, and breast cancer mortality: a population-based analysis.

BACKGROUND: In some countries, breast cancer age-standardised mortality rates have decreased by 2-4% per year since the 1990s, but others have yet to achieve this outcome. In this study, we aimed to characterise the associations between national health system characteristics and breast cancer age-standardised mortality rate, and the degree of breast cancer downstaging correlating with national age-standardised mortality rate reductions. METHODS: In this population-based study, national age-standardised mortality rate estimates for women aged 69 years or younger obtained from GLOBOCAN 2020 were correlated with a broad panel of standardised national health system data as reported in the WHO Cancer Country Profiles 2020. These health system characteristics include health expenditure, the Universal Health Coverage Service Coverage Index (UHC Index), dedicated funding for early detection programmes, breast cancer early detection guidelines, referral systems, cancer plans, number of dedicated public and private cancer centres per 10 000 patients with cancer, and pathology services. We tested for differences between continuous variables using the non-parametric Kruskal-Wallis test, and for categorical variables using the Pearson χ2 test. Simple and multiple linear regression analyses were fitted to identify associations between health system characteristics and age-standardised breast cancer mortality rates. Data on TNM stage at diagnosis were obtained from national or subnational cancer registries, supplemented by a literature review of PubMed from 2010 to 2020. Mortality trends from 1950 to 2016 were assessed using the WHO Cancer Mortality Database. The threshold for significance was set at a p value of 0·05 or less. FINDINGS: 148 countries had complete health system data. The following variables were significantly higher in high-income countries than in low-income countries in unadjusted analyses: health expenditure (p=0·0002), UHC Index (p<0·0001), dedicated funding for early detection programmes (p=0·0020), breast cancer early detection guidelines (p<0·0001), breast cancer referral systems (p=0·0030), national cancer plans (p=0·014), cervical cancer early detection programmes (p=0·0010), number of dedicated public (p<0·0001) and private (p=0·027) cancer centres per 10 000 patients with cancer, and pathology services (p<0·0001). In adjusted multivariable regression analyses in 141 countries, two health system characteristics were significantly associated with lower age-standardised mortality rates: higher UHC Index levels (ß=-0·12, 95% CI -0·16 to -0·08) and increasing numbers of public cancer centres (ß=-0·23, -0·36 to -0·10). These findings indicate that each unit increase in the UHC Index was associated with a 0·12-unit decline in age-standardised mortality rates, and each additional public cancer centre per 10 000 patients with cancer was associated with a 0·23-unit decline in age-standardised mortality rate. Among 35 countries with available breast cancer TNM staging data, all 20 that achieved sustained mean reductions in age-standardised mortality rate of 2% or more per year for at least 3 consecutive years since 1990 had at least 60% of patients with invasive breast cancer presenting as stage I or II disease. Some countries achieved this reduction without most women having access to population-based mammographic screening. INTERPRETATION: Countries with low breast cancer mortality rates are characterised by increased levels of coverage of essential health services and higher numbers of public cancer centres. Among countries achieving sustained mortality reductions, the majority of breast cancers are diagnosed at an early stage, reinforcing the value of clinical early diagnosis programmes for improving breast cancer outcomes. FUNDING: None.