The number of cancer survivors continues to increase because of both advances in early detection and treatment and the aging and growth of the population. For the public health community to better serve these survivors, the American Cancer Society and the National Cancer Institute collaborate to estimate the number of current and future cancer survivors using data from the Surveillance, Epidemiology, and End Results cancer registries. In addition, current treatment patterns for the most prevalent cancer types are presented based on information in the National Cancer Data Base and treatment-related side effects are briefly described. More than 15.5 million Americans with a history of cancer were alive on January 1, 2016, and this number is projected to reach more than 20 million by January 1, 2026. The 3 most prevalent cancers are prostate (3,306,760), colon and rectum (724,690), and melanoma (614,460) among males and breast (3,560,570), uterine corpus (757,190), and colon and rectum (727,350) among females. More than one-half (56%) of survivors were diagnosed within the past 10 years, and almost one-half (47%) are aged 70 years or older. People with a history of cancer have unique medical and psychosocial needs that require proactive assessment and management by primary care providers. Although there are a growing number of tools that can assist patients, caregivers, and clinicians in navigating the various phases of cancer survivorship, further evidence-based resources are needed to optimize care. CA Cancer J Clin 2016;66:271-289. © 2016 American Cancer Society.

https://onlinelibrary.wiley.com/doi/pdf/10.3322/caac.21349

Cancer treatment and survivorship statistics, 2016.

Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.

/pdf/microenvironmental-regulation-of-tumor-progression-and-4528oymlw6.pdf

Microenvironmental regulation of tumor progression and metastasis.

Background Enzalutamide (formerly called MDV3100) targets multiple steps in the androgen-receptor–signaling pathway, the major driver of prostate-cancer growth. We aimed to evaluate whether enzalutamide prolongs survival in men with castration-resistant prostate cancer after chemotherapy. Methods In our phase 3, double-blind, placebo-controlled trial, we stratified 1199 men with castration-resistant prostate cancer after chemotherapy according to the Eastern Cooperative Oncology Group performance-status score and pain intensity. We randomly assigned them, in a 2:1 ratio, to receive oral enzalutamide at a dose of 160 mg per day (800 patients) or placebo (399 patients). The primary end point was overall survival. Results The study was stopped after a planned interim analysis at the time of 520 deaths. The median overall survival was 18.4 months (95% confidence interval [CI], 17.3 to not yet reached) in the enzalutamide group versus 13.6 months (95% CI, 11.3 to 15.8) in the placebo group (hazard ratio for de...

/pdf/increased-survival-with-enzalutamide-in-prostate-cancer-1v77512mc7.pdf

Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy

The number of cancer survivors continues to increase in the United States because of the growth and aging of the population as well as advances in early detection and treatment. To assist the public health community in better serving these individuals, the American Cancer Society and the National Cancer Institute collaborate every 3 years to estimate cancer prevalence in the United States using incidence and survival data from the Surveillance, Epidemiology, and End Results cancer registries; vital statistics from the Centers for Disease Control and Prevention's National Center for Health Statistics; and population projections from the US Census Bureau. Current treatment patterns based on information in the National Cancer Data Base are presented for the most prevalent cancer types. Cancer-related and treatment-related short-term, long-term, and late health effects are also briefly described. More than 16.9 million Americans (8.1 million males and 8.8 million females) with a history of cancer were alive on January 1, 2019; this number is projected to reach more than 22.1 million by January 1, 2030 based on the growth and aging of the population alone. The 3 most prevalent cancers in 2019 are prostate (3,650,030), colon and rectum (776,120), and melanoma of the skin (684,470) among males, and breast (3,861,520), uterine corpus (807,860), and colon and rectum (768,650) among females. More than one-half (56%) of survivors were diagnosed within the past 10 years, and almost two-thirds (64%) are aged 65 years or older. People with a history of cancer have unique medical and psychosocial needs that require proactive assessment and management by follow-up care providers. Although there are growing numbers of tools that can assist patients, caregivers, and clinicians in navigating the various phases of cancer survivorship, further evidence-based resources are needed to optimize care.

https://onlinelibrary.wiley.com/doi/pdf/10.3322/caac.21565

Cancer treatment and survivorship statistics, 2019

Bevacizumab plus Irinotecan,Fluorouracil,and Leucovorin for Metastatic Colorectal Cancer

Traditionally, androgen deprivation therapy (ADT) has been the standard initial treatment for metastatic hormone-sensitive prostate cancer (mHSPC), with chemotherapy utilized in the castration-resistant setting. Data reported from three recent clinical trials shed new light on the role of upfront docetaxel in advanced or mHSPC. Two of these studies-CHAARTED and STAMPEDE-showed significant improvement in overall survival, while the third study, GETUG-AFU 15, showed no statistical difference. The CHAARTED study showed a 13.6-month survival improvement and the STAMPEDE study showed a 10-month survival improvement with ADT plus docetaxel, compared with ADT alone, in the hormone-sensitive setting. These numbers are remarkable when compared with the 2.9-month survival benefit from docetaxel in the metastatic castration-resistant setting, which has been the standard setting for the use of docetaxel in advanced prostate cancer. In this review, we describe the historical data for chemotherapy in the perioperative and metastatic prostate cancer settings, and the recent trials that are changing the paradigm in support of docetaxel in the upfront setting.

Upfront Chemotherapy for Metastatic Prostate Cancer.

Long awaited data from the clinical investigation of bladder cancer in both the neoadjuvant and adjuvant settings were released in 2011, setting the stage for the next generation of work in this area. The findings of a number of studies provide the first steps towards a personalized approach to this disease.

Bladder cancer in 2011: The dawn of personalized medicine

The androgen receptor (AR) is a ligand-inducible transcription factor that regulates target gene expression. Androgen signaling has been considered a putative explanation for gender differences in urothelial carcinoma (UC) incidence. In the absence of established risk factors, men still experience a threefold risk of UC as compared to women. Multiple investigations to modulate the AR have been performed with in vitro and in vivo models of UC. Down-regulation of the AR has been shown to inhibit UC growth through increased apoptosis, decreased cell proliferation, and decreased cell migration. AR activation up-regulates EGFR and HER2/neu expression contributing to UC progression. UC is more easily induced in male than female models and the incidence of chemically-induced UC is decreased by castration and the addition of estrogens; it is increased by testosterone. Epithelial to mesenchymal transition (EMT) has been postulated to be androgen-driven in UC and affects chemotherapy sensitivity. UC has not achieved the same therapeutic advances that have been seen in other tumor types in recent years. Androgen-driven events may account for some of the treatment resistance seen in this tumor type. Novel agents which disrupt androgen synthesis and/or AR signaling are in development and some (abiraterone, enzalutamide) are approved for advanced prostate cancer. Biomarker AR-driven clinical trials of highly effective anti-androgen therapy (HEAT) agents in UC present a promising picture.

The Epidemiological, Mechanistic and Potential Clinical Role of Androgen Receptor (AR) in Urothelial Carcinoma

TPS587 Background: The current standard of care for patients (pts) with newly diagnosed MIBC is neoadjuvant cisplatin (cis)-based chemotherapy followed by radical cystectomy and pelvic lymph node dissection (RC+PLND). For the 20-50% pts who are cis-ineligible, the current standard of care is RC+PLND alone (Galsky Future Oncol 2021). Adjuvant therapy is currently recommended for cis-ineligible patients with high-risk features at cystectomy. Due to the high rates of recurrence in cis-ineligible pts with RC+PLND alone, there is a need to develop new therapies in this setting. Enfortumab vedotin (EV), an antibody-drug conjugate, delivers the microtubule-disrupting agent monomethyl auristatin E to cells expressing Nectin-4, which is highly expressed in urothelial cancer. In EV-301, a phase 3 study, EV showed an overall survival (OS) benefit vs chemotherapy in pts with locally advanced (la) or metastatic urothelial carcinoma (mUC) who had previously received platinum-based therapy and a PD-1 or PD-L1 inhibitor (Powles NEJM 2021). EV has also demonstrated activity and a tolerable safety profile in cis-ineligible pts with la/mUC (Yu Lancet Oncol 2021). Given the efficacy of EV in la/mUC, it is being evaluated as perioperative therapy in cis-ineligible MIBC in EV-103 cohort L. Methods: Study EV-103 (NCT03288545) la/mUC and MIBC cohorts were described previously (Hoimes ASCO 2019; Hoimes ASCO-GU 2020). Cohort L was added to evaluate EV monotherapy (n = 50) as perioperative therapy in cis-ineligible pts with MIBC (cT2-T4aN0M0 or cT1-T4aN1M0). Eligible pts are previously untreated for MIBC, ECOG 0-2, have CrCl ≥30 mL/min, and are medically fit for and agree to undergo curative intent RC+PLND. Pts with pT1 disease are eligible only if they have N1 disease. Pts receive 3 cycles of neoadjuvant EV (1.25 mg/kg IV) on Days 1 and 8 of each 3-week cycle, followed by RC+PLND and then 6 cycles of adjuvant EV starting 8 weeks post-RC on the same schedule. Pathological complete response rate per central pathology review is the primary endpoint. Secondary endpoints include event-free survival and disease-free survival by blinded independent central review and investigator, pathological downstaging rate per central pathology review, OS, safety and tolerability. Cohort L is currently enrolling pts in the US and Canada. Clinical trial information: NCT03288545.

Study EV-103 cohort L: Evaluating perioperative enfortumab vedotin monotherapy in cis-ineligible muscle invasive bladder cancer (MIBC) (trial in progress).

BACKGROUND
Neoadjuvant chemotherapy (NAC) is the standard of care in muscle-invasive bladder cancer (MIBC). However, treatment is intense, and the overall benefit is small, necessitating effective biomarkers to identify patients who will benefit most.


OBJECTIVE
To characterize cell-free DNA (cfDNA) methylation in patients receiving NAC in SWOG S1314, a prospective cooperative group trial, and to correlate the methylation signatures with pathologic response at radical cystectomy.


DESIGN, SETTING, AND PARTICIPANTS
SWOG S1314 is a prospective cooperative group trial for patients with MIBC (cT2-T4aN0M0, ≥5 mm of viable tumor), with a primary objective of evaluating the coexpression extrapolation (COXEN) gene expression signature as a predictor of NAC response, defined as achieving pT0N0 or ≤pT1N0 at radical cystectomy. For the current exploratory analysis, blood samples were collected prospectively from 72 patients in S1314 before and during NAC, and plasma cfDNA methylation was measured using the Infinium MethylationEPIC BeadChip array.


INTERVENTION
No additional interventions besides plasma collection.


OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Differential methylation between pathologic responders (≤pT1N0) and nonresponders was analyzed, and a classifier predictive of treatment response was generated using the Random Forest machine learning algorithm.


RESULTS AND LIMITATIONS
Using prechemotherapy plasma cfDNA, we developed a methylation-based response score (mR-score) predictive of pathologic response. Plasma samples collected after the first cycle of NAC yielded mR-scores with similar predictive ability. Furthermore, we used cfDNA methylation data to calculate the circulating bladder DNA fraction, which had a modest but independent predictive ability for treatment response. In a model combining mR-score and circulating bladder DNA fraction, we correctly predicted pathologic response in 79% of patients based on their plasma collected at baseline and after one cycle of chemotherapy. Limitations of this study included a limited sample size and relatively low circulating bladder DNA levels.


CONCLUSIONS
Our study provides the proof of concept that cfDNA methylation can be used to generate classifiers of NAC response in bladder cancer patients.


PATIENT SUMMARY
In this exploratory analysis of S1314, we demonstrated that cell-free DNA methylation can be profiled to generate biomarker signatures associated with neoadjuvant chemotherapy response. With validation in additional cohorts, this minimally invasive approach may be used to predict chemotherapy response in locally advanced bladder cancer and perhaps also in metastatic disease.

Cell-free DNA Methylation as a Predictive Biomarker of Response to Neoadjuvant Chemotherapy for Patients with Muscle-invasive Bladder Cancer in SWOG S1314.

Thomas W. Flaig

Papers

Upfront Chemotherapy for Metastatic Prostate Cancer.

Bladder cancer in 2011: The dawn of personalized medicine

The Epidemiological, Mechanistic and Potential Clinical Role of Androgen Receptor (AR) in Urothelial Carcinoma

Study EV-103 cohort L: Evaluating perioperative enfortumab vedotin monotherapy in cis-ineligible muscle invasive bladder cancer (MIBC) (trial in progress).

Cell-free DNA Methylation as a Predictive Biomarker of Response to Neoadjuvant Chemotherapy for Patients with Muscle-invasive Bladder Cancer in SWOG S1314.