Background: Significant changes in renal cell carcinoma (RCC) drug treatment and improved access to abdominal imaging have recently been implemented. The impact of these changes on patient characteristics and prognosis remains to be quantified. Methods: A population-based cohort of 210,418 RCC cases from the Centre for Cancer Registry Data (ZfKD) diagnosed in Germany between 2000 and 2019 was analyzed in this observational study. Three time periods of diagnosis were defined, the first (2000-2005) functioning as a control. The remaining were defined according to the introduction of tyrosine kinase targeting drugs (2006-2014) and checkpoint inhibitor drugs (2015-2019). Five-year relative survival (RS) trends for each risk group and metastatic RCC (mRCC) were determined using Poisson regression models. Results: Age at diagnosis and the proportion of low-risk disease increased, while the proportion of mRCC decreased (p < 0.0001). RS improved slightly between the first and last period in low (5-year RS 98.7% vs. 100.9%), intermediate (89.2% vs. 91.9%), and high-risk (76.6% vs. 80.3%), as well as mRCC (28.3% vs. 29.1%). The overall change in prognosis was significant in low (p = 0.0233) and high-risk groups (p = 0.0002), but not in intermediate-risk and mRCC groups. In a multivariate analysis, high-risk ccRCC patients appear to profit from drug treatment advances. Conclusions: Earlier detection has improved prognosis for the majority of RCC patients. Further efforts should be aimed at diagnosing more mRCC patients earlier, when surgical tumor removal remains feasible.

Background An increased risk for breast cancer (BC) following hormone replacement therapy (HT) with estrogen and progesterone in women has been reported in several studies. However, HTs are associated with two distinct effects, a BC risk (RF) and an acceleration of BC growth (GAF). The interaction of both effects is analyzed. Methods Using data from the U.S. population on BC incidence and life expectancy specific cohorts and their disease trajectories are modelled. First, age-specific BCs are randomly generated for the age interval 50-80 years based on public data. Second, this simulated cohort subsequently receives a HT over 4 years that accelerates the growth of prevalent BCs. In a third cohort additional BCs are simulated caused by HT under treatment. The cumulative incidence of BCs is modelled for up to 30 years using different assumptions on BC growth duration, GAF and RF, as well as the duration of HT. The Womens Health Initiative Study (WHI-S) is also simulated in a fourth cohort assuming a GAF 1.4 and RF 2.0. Results Studies modelling the risk of BC after HT imply two main findings: First, the growth of prevalent BCs is accelerated in parallel to the start of HT. This results in an increased BC incidence where the relative risk is equivalent to the GAF. The duration of HT defines the turning point of this increase. The second finding demonstrates that during the 15 years of BC growth an inherent RF for BC through HTs becomes observable only after a comparable delay. The combined effect results in an overlap of age-specific BCs, which develop at the same time, both growing faster under HT. Varying parameters can explain different results in the WHI-S. According to the WHI almost 6 million women decided to discontinue or not to start HT. This offers a valid explanation (assuming a GAF 2) for the 10% decline in incidence around 2002. Estimates which report one million additional BCs associated with HT in Western countries since 1990 can thus, for the most part, be attributed to more rapidly growing prevalent BCs. Conclusion HT accelerates the growth of prevalent BCs and can also cause BCs which become symptomatic after 10 or more years. In combination these effects increase BC incidence. Differentiated information on these inherent risks and benefits should support shared decision-making for HT. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used only openly available human data that were originally located at: http://seer.cancer.gov/ https://seer.cancer.gov/statistics-network/ http://www.tumorregister-muenchen.de/en/facts/specific_analysis.php I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced are available online at: http://seer.cancer.gov/ https://seer.cancer.gov/statistics-network/ http://www.tumorregister-muenchen.de/en/facts/specific_analysis.php

Background A growing breast cancer (BC) is associated with an inherent risk of metastasis (MET). If surgical treatment of a BC is delayed, the prognosis worsens continuously with increasing tumor diameter (TD). This frequently overlooked topic in healthcare is currently the subject of debate. Methods Population-based data on BC incidence and surgery waiting period for the U.S. and Germany are used to examine the resulting risks. BC growth and initiation of MET are calculated in a simulation approach using hormone receptor status (HR), tumor volume doubling time (VDT), and TD-dependent survival. Results The U.S. and Germany report 287,850/71,375 BCs annually. Based on an initial mean TD of 19.8mm 15-year mortality in both countries is estimated using a Gompertz function at 19.6% without surgical delay. VDT of HR+ and HR- BCs differs by a factor of 2.4, leading to an estimated mortality increase of 1.34/3.26% (HR+/HR-) if all surgical procedures are pushed back by five weeks. The mean delay in the U.S. and Germany is 33.7/26.0 days respectively. Prolonged waiting periods lead to estimated 4,676/918 additional BC deaths or a 1.6/1.2% rise in BC mortality rate. Further increases are due to MET relapse up to 25 years after diagnosis. Conclusions A growing tumor can continuously initiate MET with every millimeter. The results of this study offer replicable and valid evidence, based on publicly available clinical and population-based data, that confirmed BCs should be treated according to HR status as soon as possible.### Competing Interest StatementThe authors have declared no competing interest.### Funding StatementThis study did not receive any funding### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The study used ONLY openly available human data that were originally located at: SEER: https://seer.cancer.gov/statistics-network/ RKI: https://www.krebsdaten.de/Krebs/SiteGlobals/Forms/Datenbankabfrage/datenbankabfrage\_stufe2\_form.html MCR: http://www.tumorregister-muenchen.de/en/facts/specific_analysis.phpI confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesThe datasets used to support the results of this study are publicly available (SEER, RKI, publications). Data from the MCR are protected by data privacy protection jurisdiction but may be made available in anonymized form on reasonable request.

COVID-19 has led to treatment shortages and delays.Under these extraordinary circumstances oncologic procedures and treatments had to be postponed.In most cases no patients were acutely harmed.However, a growing tumor carries an inherent risk of metastasis that increases with each delay.In breast cancer (BC) this risk can be calculated.BC mortality is attributed to distant metastasis, therefore the metastatic risk can be estimated by describing the relationship between tumor diameter and mortality using a Gompertz function derived from previously published literature 1,2 and population-based data (Munich Cancer Registry).The starting time can either be a palpatory finding with subsequent diagnostic workup or a screening mammography.For screening the delay is summed starting from the time the patient is informed, through the follow-up appointment, the biopsy procedure, the tumor board recommendation, and until the first day of treatment.This function is based on the parameters tumor diameter at primary treatment, volume doubling times (VDT), length of time between initial diagnosis and primary therapy in days, and metastatic risk.The resulting function estimates 15-year mortality according to tumor diameter as described in our previous work. 3e used VDT1 of 103/241 days for HR-(negative)/ HR+ (positive) BC obtained via ultrasound by Ryu EB. 1 In addition, we used the 25%/75% percentiles for VDT2 of 41/99 days derived from screening data by The ratio between HR+/HR-BCs of the VDT1/2 values is 2.33/2.41 and based on our previous work fittingly corresponds to the ratio of median time to metastasis in HR+/HR-BCs. 4 The mean of these two literature-based VDT1 and 2 is modeled and shown as a third group (VDT3) representing a more moderate estimate for VDT.The following function uses VDT3 to estimate 15-year mortality: GF 15-yr Mortality (a : 58.4,b : 4.46,c : 0.

If a mammography screening program (MS) is to be expanded, the benefit must be demonstrated for each additional age cohort. For the age interval between 40 and 80 years, the association between tumor-related and tumor-independent mortality of 21 2-year cohorts is modeled using up-to-date, valid data to determine MS outcome. Disease trajectories with and without biennial MS are extrapolated for each age cohort using the available data and knowledge on MS. The competing mortality is randomly generated for each age cohort with and without MS for a follow-up period of 20 years. Analyses of the modeled cohorts describe incremental change for each year, quantifying the changing benefits of MS. With increasing age, the proportion of tumor-independent mortality before and with metastatic disease increases and the benefit decreases. The simulations with 21 studies on the age interval 40–80 years provide four parameters to determine the benefits and costs of MS: The number of prevented deaths, required mammography screening exams (MSE) and their costs, life-years gained, and the required MSEs. If one additional MSE is offered for age groups 48/70 years, this will result in 311/320 prevented breast cancer (BC) deaths with 1742/1494 required MSEs or 8784/4168 life-years gained with 64/140 required MSEs. A rational cutoff cannot be quantified. The mortality effect of MS between 40 and 80 years is quantified in 21 steps using two metrics, number of MSEs per tumor-related mortality prevented and per life-year gained. This provides a decision support for stepwise expansions. Given this real-world evidence no rational age cutoffs for MS becomes evident. A society has to decide which MS costs, including side effects of MS for women who remain BC-free, it is willing and able to accept in order to reduce breast cancer mortality.

Background: If a mammography screening program is to be expanded, the benefit must be demonstrated for each additional age cohort. For the age interval between 40 to 80 years, the association between tumor-related and tumor-independent mortality of 21 two-year cohorts is described in this modeling study using up-to-date, valid data determining mammography screening (MS) success. Methods: Disease trajectories with and without biennial MS are modeled for each age cohort. Data for modeling are MS cohort size, age-specific incidence, survival as a function of prognostic factors, prognostic factors with and without MS, and population mortality. For a follow-up of 20 years, the competing mortality is randomly generated for each age cohort with and without MS. Analysis of the 21 study cohorts describes incremental changes in the benefits of MS. Findings: With the generation of disease trajectories, six patient-relevant outcomes emerge. With increasing age, the proportion of tumor-independent mortality before and under metastasis increases and the benefit decreases. Results for the 21 age-specific trials show that with 10 or 11 biennial MS, the greatest benefit is achieved with screening intervals between the ages 52 to 71 or 52 to 73.Interpretation: The mortality effect of MS can be quantified using two metrics, number of MS per tumor-related mortality prevented and per life-year gained. There are no rational age cutoffs for MS. A society has to decide what costs it is willing and able to pay for MS in order to reduce breast cancer mortality.Funding Information: None.Declaration of Interests: The authors declare no conflicts of interests.

Purpose Growing primary breast cancers (PT) can initiate local recurrences (LR), regional lymph nodes (pLN) and distant metastases (MET). Components of these progressions are initiation, frequency, growth duration, and survival. These characteristics describe principles which proposed molecular concepts and hypotheses must align with. Methods In a population-based retrospective modeling approach using data from the Munich Cancer Registry key steps and factors associated with metastasis were identified and quantified. Analysis of 66.800 patient datasets over four time periods since 1978, reliable evidence is obtained even in small subgroups. Together with results of clinical trials on prevention and adjuvant treatment (AT) principles for the MET process and AT are derived. Results The median growth periods for PT/MET/LR/pLN comes to 12.5/8.8/5/3.5 years, respectively. Even if 30% of METs only appear after 10 years, a pre-diagnosis MET initiation principle not a delayed one should be true. The growth times of PTs and METs vary by a factor of 10 or more but their ratio is robust at about 1.4. Principles of AT are 50% PT eradication, the selective and partial eradication of bone and lung METs. This cannot be improved by extending the duration of the previously known ATs. Conclusion A paradigm of ten principles for the MET process and ATs is derived from real world data and clinical trials indicates that there is no rationale for the long-term application of endocrine ATs, risk of PTs by hormone replacement therapies, or cascading initiation of METs. The principles show limits and opportunities for innovation also through alternative interpretations of well-known studies. The outlined MET process should be generalizable to all solid tumors.

Purpose Despite national and international guideline recommendations, few studies have been conducted to estimate the impact of colonoscopy screening on long-term colorectal cancer incidence. Aim of this study was to determine the long-term impact of a full colonoscopy with polypectomy on colorectal cancer incidence in a large screening population. Methods In this prospective observational cohort study, a total of 10,947 colonoscopy screening participants from within the scope of the Munich Cancer Registry were consecutively recruited from participating gastroenterology practices and their subsequent colorectal cancer incidence assessed. Predictive factors associated with colorectal cancer were also evaluated in univariate and multivariate analyses. Results After a median follow-up of 14.24 years (95% CI [14.21–14.25]), 93 colorectal cancer cases were observed. This is equivalent to a truncated age-standardized rate of 69.0 (95% CI [43.3–94.7]) for male and 43.4 (95% CI [29.4–57.5]) for female participants (≥ 50 years at colonoscopy). The ratio of this observed to the expected rate from cancer registry data showed a 67% decrease in colorectal cancer incidence in the male and 65% in the female participants ( p < 0.0001). In multivariate analysis of screening patients, age at screening ( p < 0.0001) was the main predictive factor for colorectal cancer. In the subgroup with positive polyp findings, age ( p < 0.0001) and the polyp size ( p = 0.0002) were associated with colorectal cancer. Conclusion These results underline the significance of a full colonoscopy screening combined with polypectomy in reducing the total disease burden of colorectal cancer.

Purpose In breast cancer (BC), the duration of endocrine adjuvant therapies (AT) has been extended continuously up to 10 years. We present an alternative explanation for the effect, which could enable shorter treatments. Method The relevant literature on chemoprevention and (neo-)adjuvant therapy was reviewed. Data for initiation and growth of primary and contralateral BCs and their metastases (MET) were considered. Also, population-based data from the Munich Cancer Registry for MET-free survival, time trends of MET patterns, and survival achieved by improved ATs are used to estimate all events in the long-term follow-up. Results Extended ATs (EAT) that continue after 1, 2, or 5 years reduce mortality only slightly. The effect is delayed, occurring more than 5 years after extension. EATs does not affect the prognosis of 1stBCs, they preventively eradicate contralateral 2ndBCs and thus their future life-threatening METs. Because chemoprevention can eradicate BCs from the smallest clusters to almost detectable BCs, ATs can be temporarily suspended without imposing harm. Results equal to EATs can be achieved by short-term ATs of the 1stBC and by repeated neo-ATs targeted at the indefinitely developing 2ndBCs. Considering this potential in de-escalation, a 70–80% reduction of overtreatment seems possible. Conclusion Knowledge of initiation and growth of tumors with known effects of neo-ATs suggest that intermittent endocrine ATs may achieve the same results as EATs but with improved quality of life and survival because of fewer side effects and better compliance. The challenge for developments of repeated ATs becomes: how short is short enough.

Background: Available data on accelerated proliferation and increased breast cancer risk due to hormone replacement therapy (HT) are inconsistent. Data on long-term effects of HT are limited. The interaction between several key factors was examined using a model-based approach. Methods: Cohorts of 50 year old women, BCs were randomly generated for 30 years based on the age-specific incidence. A control group received a HT that increased the growth of occult BCs. In a 3rd cohort BCs were additionally induced by HT. This model illustrates the interrelationship of important parameters and allows the simulation and comparison of previously published clinical studies. Results: Using plausible parameters for BC growth factor (GF) and HT-related effects it was demonstrated that HT caused accelerated growth of occult BCs with an apparent increase in incidence and shortened time to diagnosis. The Womens Health Initiative (WHI) study was reconstructed assuming a GF of 1.43 induced by HT. The decision of millions of women to discontinue or forego HT based on the published risks of the WHI-study in 2002 could explain the marked jump of 6.7% in incidence within a few months. If additional BCs were induced by HT, then these BCs may become apparent after 10 or more years together with those appearing according to the normal incidence. At this time conclusive data on type, timing, and molecular characteristics of HT induced BCs are not yet available. Conclusion: The acceleration in growth of occult BC has been underestimated. Initially HTs can cause an apparent increase in BC incidence thereby explaining the WHI-dependent decrease in 2003. A HT associated BC risk should only be detectable with a delay of ten and more years.

•Data on the number of positive LNs as a function of tumor diameter in HR + breast cancer.•Shows a uniform, accelerating LN infiltration by growing primary tumors.•Supports a parallel MET initiation, not caused by positive lymph nodes.•Provides estimates of MET in negative LNs as a function of tumor diameter.•Can explain effects and limits of adjuvant therapies.

Die Zertifizierung onkologischer Zentren durch die Deutsche Krebsgesellschaft ist beispielhaft. Dennoch stoßen viele autonome Kliniken an ihre Grenzen, wenn es um die Erhebung, aber auch Übermittlung von Langzeitdaten geht. Die Vernetzung der Zentren könnte dazu beitragen, diese zu entlasten.

Ziele: Das Ziel dieser offiziellen Leitlinie, die von der Deutschen Gesellschaft fur Gynakologie und Geburtshilfe (DGGG) und der Deutschen Krebsgesellschaft (DKG) publiziert und koordiniert wurde, ist es, die Fruherkennung, Diagnostik, Therapie und Nachsorge des Mammakarzinoms zu optimieren. Methoden: Der Aktualisierungsprozess der S3-Leitlinie aus 2012 basierte zum einen auf der Adaptation identifizierter Quellleitlinien und zum anderen auf Evidenzubersichten, die nach Entwicklung von PICO-(Patients/Interventions/Control/Outcome-)Fragen, systematischer Recherche in Literaturdatenbanken sowie Selektion und Bewertung der gefundenen Literatur angefertigt wurden. In den interdisziplinaren Arbeitsgruppen wurden auf dieser Grundlage Vorschlage fur Empfehlungen und Statements erarbeitet, die im Rahmen von strukturierten Konsensusverfahren modifiziert und graduiert wurden. Empfehlungen: Der Teil 1 dieser Kurzversion der Leitlinie zeigt Empfehlungen zur Fruherkennung, Diagnostik und Nachsorge des Mammakarzinoms: Der Stellenwert des Mammografie-Screenings wird in der aktualisierten Leitlinienversion bestatigt und bildet damit die Grundlage der Fruherkennung. Neben den konventionellen Methoden der Karzinomdiagnostik wird die Computertomografie (CT) zum Staging bei hoherem Ruckfallrisiko empfohlen. Die Nachsorgekonzepte beinhalten Untersuchungsintervalle fur die korperliche Untersuchung, Ultraschall und Mammografie, wahrend weiterfuhrende Geratediagnostik und Tumormarkerbestimmungen bei der metastasierten Erkrankung Anwendung finden.

Purpose The aim of this official guideline coordinated and published by the German Society for Gynecology and Obstetrics (DGGG) and the German Cancer Society (DKG) was to optimize the screening, diagnosis, therapy and follow-up care of breast cancer. Method The process of updating the S3 guideline published in 2012 was based on the adaptation of identified source guidelines. They were combined with reviews of evidence compiled using PICO (Patients/Interventions/Control/Outcome) questions and with the results of a systematic search of literature databases followed by the selection and evaluation of the identified literature. The interdisciplinary working groups took the identified materials as their starting point and used them to develop suggestions for recommendations and statements, which were then modified and graded in a structured consensus process procedure. Recommendations Part 2 of this short version of the guideline presents recommendations for the therapy of primary, recurrent and metastatic breast cancer. Loco-regional therapies are de-escalated in the current guideline. In addition to reducing the safety margins for surgical procedures, the guideline also recommends reducing the radicality of axillary surgery. The choice and extent of systemic therapy depends on the respective tumor biology. New substances are becoming available, particularly to treat metastatic breast cancer.