A Phase II Study of Rucaparib Monotherapy in Nonmetastatic, Hormone-Sensitive Prostate Cancer Demonstrating "BRCAness" Genotype (ROAR).

BACKGROUND: Both germline and somatic BReast CAncer gene (BRCA) mutations are poor prognostic markers in men with localized or metastatic prostate cancer. For instance, men with these mutations often are diagnosed with prostate cancer earlier and develop metastatic disease earlier compared with those who do not harbor similar mutations. Patients with germline alterations typically have more advanced disease and shorter overall survival (Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31(14):1748-1757. doi:10.1200/JCO.2012.43.1882). The risk of disease progression to metastatic disease is significant in patients with this genotype of prostate cancer. The percentage of patients free from metastatic disease was 90%, 72%, and 50%, respectively, compared with 97%, 94%, and 84% at 3, 5, and 10 years for patients with intact DNA repair (P < .001) (Castro E, Goh C, Leongamornlert D, et al. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer. Eur Urol. 2015;68(2):186-193. doi: 10.1016/j.eururo.2014.10.022). DNA damage repair non-BRCA mutations include alterations in genes such as ATM, CHEK2, PALB2, and RAD51. While less common than BRCA mutations, they have emerged as significant prognostic markers in prostate cancer. These BRCAness mutations are associated with a higher risk of aggressive disease and poorer survival outcomes. Given the debilitating physical and psychological side effects of androgen deprivation therapy (ADT) in relatively younger men with prostate cancer, delaying ADT in these men may be an attractive strategy. Given the proven efficacy of polyadenosine diphosphate-ribose polymerase (PARP) inhibitors in the castration-resistant prostate cancersetting, PARP inhibitor monotherapy in a nonmetastatic castration-sensitive (nmCSPC) setting has the potential to delay metastasis and delay the onset of ADT related symptoms. METHODS: This is a single-arm, single-center, open-label, phase II trial to assess the efficacy of rucaparib in patients with high-risk biochemically recurrent (BCR) nmHSPC, which was defined as PSA doubling time of <9 months, demonstrating a "BRCAness" genotype (BRCA1/2 and other homologous recombination repair mutations). A total of 15 patients were intended to be enrolled, with an expected enrollment duration of 12 months. Patients were given rucaparib 600 mg orally twice daily and were allowed to remain on study treatment until PSA progression defined by Prostate Cancer Working Group 3, with 2 years of follow-up after study treatment. We anticipated a total of 2-3 years until completion of the clinical trial. The primary endpoint was to assess the PSA progression-free survival (PSA-PFS). The secondary endpoints of the study were safety, the proportion of patients with a PSA 50% response (PSA 50), and an undetectable PSA. A 4-week treatment duration comprised one cycle. RESULTS: The study started enrolling in June 2019 and was prematurely terminated in June 2022 after the accrual of 7 patients because of changing standard of care treatments with the introduction of next-generation scans, eg, prostate-specific membrane antigen positron emission tomography (PSMA-PET). Seven patients were enrolled in the study with the following pathogenic alterations: ATM (n = 3), BRCA2 (n = 2), BRCA1 (n = 1), BRIP1 (n = 1), and RAD51 (n = 1). The median duration of follow-up was 18 months. A median of 20 cycles (range 4-42) was completed, median PSA-PFS was 35.37 months (95% CI, 0-85.11 months). In total, 2 patients achieved PSA50; both also achieved nadir PSA as undetectable. Grade ≥ 3 adverse events (AEs) were anemia and rash (in 1 patient each). No dose-limiting toxicities or severe AEs were seen. CONCLUSION: Rucaparib demonstrated acceptable toxicity and efficacy signal as an ADT-sparing approach in patients with biochemically recurrent nonmetastatic prostate cancer. It is currently challenging to understand the optimal value of systemic therapy in this disease setting due to the rapidly changing standard of care. Additionally, there are relatively few patients with BRCAness who present with nonmetastatic hormone-sensitive prostate cancer (ClinicalTrials.gov Identifier: NCT03533946).

Effect of cumulative dose of brentuximab vedotin maintenance in relapsed/refractory classical Hodgkin lymphoma after autologous stem cell transplant: an analysis of real-world outcomes.

Sixteen cycles of Brentuximab vedotin (BV) after autologous stem cell transplant (ASCT) in high-risk relapsed/refractory classical Hodgkin lymphoma demonstrated an improved 2-year progression-free survival (PFS) over placebo. However, most patients are unable to complete all 16 cycles at full dose due to toxicity. This retrospective, multicenter study investigated the effect of cumulative maintenance BV dose on 2-year PFS. Data were collected from patients who received at least one cycle of BV maintenance after ASCT with one of the following high-risk features: primary refractory disease (PRD), extra-nodal disease (END), or relapse <12 months (RL<12) from the end of frontline therapy. Cohort 1 had patients with >75% of the planned total cumulative dose, cohort 2 with 51-75% of dose, and cohort 3 with ≤50% of dose. The primary outcome was 2-year PFS. A total of 118 patients were included. Fifty percent had PRD, 29% had RL<12, and 39% had END. Forty-four percent of patients had prior exposure to BV and 65% were in complete remission before ASCT. Only 14% of patients received the full planned BV dose. Sixty-one percent of patients discontinued maintenance early and majority of those (72%) were due to toxicity. The 2-year PFS for the entire population was 80.7%. The 2-year PFS was 89.2% for cohort 1 (n=39), 86.2% for cohort 2 (n=33), and 77.9% for cohort 3 (n=46) (P=0.70). These data are reassuring for patients who require dose reductions or discontinuation to manage toxicity.

Hodgkin lymphoma arising in patients with chronic lymphocytic leukemia: outcomes from a large multi-center collaboration.

Chronic lymphocytic leukemia (CLL) patients who develop Hodgkin lymphoma (HL) have limited survival. No current therapeutic standard of care exists. We conducted a multi-center retrospective study of patients with Hodgkin Transformation (HT) of CLL. Clinicobiologic characteristics, treatment type, and survival outcomes were analyzed and compared with historic case series. Ninety-four patients were identified. Median age at HT was 67 years (range, 38-85). Median time from CLL diagnosis to HT was 5.5 years (range, 0-20.2). Prior to HT, patients received a median of 2 therapies for CLL (range, 0-12). As initial therapy for HT, 61% (n=62) received ABVD-based regimens (adriamycin, bleomycin, vinblastine, and dacarbazine). Seven (7%) patients received hematopoietic cell transplantation (HCT) while in first complete remission (CR1). The median number of treatments for HT per patient was 1 (range, 0-5) with 59 (61%) patients only receiving one line of therapy. After HT, patients had a median follow-up of 1.6 years (range, 0-15.1). Two-year overall survival (OS) after HT diagnosis was 72% (95%CI 62-83%). The patients who received standard ABVD-based therapy had a median OS of 13.2 years. Although limited by small sample size, the patients who underwent HCT for HT in CR1 had a similar 2-year OS (n=7; 67%) compared to patients who did not undergo HCT for HT in CR1 (n=87; 72%; p=0.46). In this multi-center study, HT patients treated with ABVD-based regimens had prolonged survival supporting the use of these regimens as standard of care for these patients.

Repeat radiation with bevacizumab and minocycline in bevacizumab-refractory high grade gliomas: a prospective phase 1 trial.

INTRODUCTION: There are no effective treatments for gliomas after progression on radiation, temozolomide, and bevacizumab. Microglia activation may be involved in radiation resistance and can be inhibited by the brain penetrating antibiotic minocycline. In this phase 1 trial, we examined the safety and effect on survival, symptom burden, and neurocognitive function of reirradiation, minocycline, and bevacizumab. METHODS: The trial used a 3 + 3 design for dose escalation followed by a ten person dose expansion. Patients received reirradiation with dosing based on radiation oncologist judgment, bevacizumab 10 mg/kg IV every two weeks, and oral minocycline twice a day. Symptom burden was measured using MDASI-BT. Neurocognitive function was measured using the COGSTATE battery. RESULTS: The maximum tolerated dose of minocycline was 400 mg twice a day with no unexpected toxicities. The PFS3 was 64.6%, and median overall survival was 6.4 months. Symptom burden and neurocognitive function did not decline in the interval between treatment completion and tumor progression. CONCLUSIONS: Minocycline 400 mg orally twice a day with bevacizumab and reirradiation is well tolerated by physician and patient reported outcomes in people with gliomas that progress on bevacizumab.

Risk of Incident Colorectal Cancer and Death After Colonoscopy: A Population-based Study in Utah.

BACKGROUND & AIMS: Colonoscopy is widely recommended for colorectal (CRC) screening in the United States, but evidence of effectiveness is limited. We examined whether exposure to colonoscopy decreases the odds of incident CRC and death from CRC in Utah. METHODS: We performed a case-control study of Utah residents, 54 to 90 years old, who received a CRC diagnosis from 2000 through 2010 (cases). Age- and sex-matched controls with no history of CRC (controls) were selected for each case. We determined receipt of colonoscopy 6 months to 10 years before the reference date for each case and control through administrative claims data. Colonoscopy exposure was compared by using conditional logistic regression. RESULTS: We identified 5128 cases and 20,512 controls; 741 cases (14%) and 5715 controls (28%) received a colonoscopy. Exposure to colonoscopy reduced the odds for a diagnosis of CRC; the odds ratios (ORs) were 0.41 for any CRC (95% confidence interval [CI], 0.38-0.44), 0.58 for proximal colon cancer (95% CI, 0.51-0.65), and 0.29 for distal colon or rectal cancer (95% CI, 0.25-0.33). This finding was consistent among sexes, age groups, and cancer stages. Similarly, in a subgroup analysis, colonoscopy was associated with decreased odds of death from CRC (OR, 0.33; 95% CI, 0.28-0.39) in both the proximal colon (OR, 0.43; 95% CI, 0.34-0.55) and distal colon or rectum (OR, 0.23; 95% CI, 0.18-0.30). CONCLUSIONS: In the population of Utah, colonoscopy is associated with a large reduction in risk of new-onset CRC and death from CRC. This reduction in risk for CRC was greatest for the distal colon and rectum, with a more modest reduction for proximal colon cancer.

Phase II study of amrubicin (SM-5887), a synthetic 9-aminoanthracycline, as first line treatment in patients with metastatic or unresectable soft tissue sarcoma: durable response in myxoid liposarcoma with TLS-CHOP translocation.

PURPOSE: Amrubicin is a third generation synthetic 9-aminoanthracycline that specifically inhibits topoisomerase II. Amrubicin preferentially concentrates in tumor cells leading to tumor cell death without causing cardiac toxicity. This phase II multicenter study was done to evaluate the efficacy and tolerability of amrubicin in advanced soft tissue sarcoma (STS). PATIENTS AND METHODS: 24 eligible patients with chemotherapy-naive metastatic or unresectable STS were treated with amrubicin 40 mg/m(2) intravenously daily for three consecutive days in 21 days cycles with growth factor support. Patients continued to receive treatment, as long as it was tolerated, in the absence of significant disease progression. The disease was followed on imaging scans every 6 weeks. The primary endpoint of the study was the best overall response rate. RESULTS: The best overall response rate was 13% in 23 evaluable patients. Median progression-free survival was 5.8 months, and median overall survival was 26 months. Grade 3 to 4 toxicities of febrile neutropenia and anemia occurred in 21% of treated patients. One patient with metastatic myxoid liposarcoma with TLS-CHOP translocation had a durable response and received 40 cycles of amrubicin. There was no significant cardiac toxicity. CONCLUSIONS: Amrubicin has efficacy comparable to doxorubicin in adult STS, is well tolerated and has no significant cardiac toxicity up to a cumulative dose of 4800 mg /m(2). Topoisomerase II inhibition with amrubicin warrants further study as a potential 'targeted therapy' for TLS-CHOP-translocated myxoid liposarcoma. Results from this trial favor the use of amrubicin for the treatment of STS.

Characteristics of missed or interval colorectal cancer and patient survival: a population-based study.

BACKGROUND & AIMS: Colorectal cancers (CRCs) diagnosed within a few years after an index colonoscopy can arise from missed lesions or the development of a new tumor. We investigated the proportion, characteristics, and factors that predict interval CRCs that develop within 6-60 months of colonoscopy. METHODS: We performed a population-based cohort study of Utah residents who underwent colonoscopy examinations from 1995 through 2009 at Intermountain Healthcare or the University of Utah Health System, which provide care to more than 85% of state residents. Colonoscopy results were linked with cancer histories from the Utah Population Database to identify patients who underwent colonoscopy 6-60 months before a diagnosis of CRC (interval cancer). Logistic regression was performed to identify risk factors associated with interval cancers. RESULTS: Of 126,851 patients who underwent colonoscopies, 2659 were diagnosed with CRC; 6% of these CRCs (159 of 2659) developed within 6 to 60 months of a colonoscopy. Sex and age were not associated with interval CRCs. A higher percentage of patients with interval CRC were found to have adenomas at their index colonoscopy (57.2%), compared with patients found to have CRC detected at colonoscopy (36%) or patients who did not develop cancer (26%) (P < .001). Interval CRCs tended to be earlier-stage tumors than those detected at index colonoscopy, and to be proximally located (odds ratio, 2.24; P < .001). Patients with interval CRC were more likely to have a family history of CRC (odds ratio, 2.27; P = .008) and had a lower risk of death than patients found to have CRC at their index colonoscopy (hazard ratio, 0.63; P < .001). CONCLUSIONS: In a population-based study in Utah, 6% of all patients with CRC had interval cancers (cancer that developed within 6 to 60 months of a colonoscopy). Interval CRCs were associated with the proximal colon, earlier-stage cancer, lower risk of death, higher rate of adenoma, and family history of CRC. These findings indicate that interval colorectal tumors may arise as the result of distinct biologic features and/or suboptimal management of polyps at colonoscopy.

Increased risk of colorectal neoplasia among family members of patients with colorectal cancer: a population-based study in Utah.

BACKGROUND & AIMS: Colorectal cancer (CRC) frequently develops in multiple members of the same families, but more data are needed to prepare effective screening guidelines. We quantified the risk of CRC and adenomas in first-degree relatives (FDRs) and second-degree relatives and first cousins of individuals with CRC, and stratified risk based on age at cancer diagnosis. METHODS: We performed a case-control study of Utah residents, 50-80 years old, who underwent colonoscopy from 1995 through 2009. Index cases (exposed to colonoscopy) were colonoscopy patients with a CRC diagnosis. Age- and sex-matched individuals, unexposed to colonoscopy (controls) were selected to form the comparison groups for determining risk in relatives. Colonoscopy results were linked to cancer and pedigree information from the Utah Population Database to investigate familial aggregation of colorectal neoplasia using Cox regression analysis. RESULTS: Of 126,936 patients who underwent a colonoscopy, 3804 were diagnosed with CRC and defined the index cases. FDRs had an increased risk of CRC (hazard rate ratio [HRR], 1.79; 95% confidence interval [CI],1.59-2.03), as did second-degree relatives (HRR, 1.32; 95% CI, 1.19-1.47) and first cousins (HRR, 1.15; 95% CI, 1.07-1.25), compared with relatives of controls. This risk was greater for FDRs when index patients developed CRC at younger than age 60 years (HRR, 2.11; 95% CI, 1.70-2.63), compared with older than age 60 years (HRR, 1.77; 95% CI, 1.58-1.99). The risk of adenomas (HRR, 1.82; 95% CI, 1.66-2.00) and adenomas with villous histology (HRR, 2.43; 95% CI, 1.96-3.01) also were increased in FDRs. Three percent of CRCs in FDRs would have been missed if the current guidelines, which stratify screening recommendations by the age of the proband, were strictly followed. CONCLUSIONS: FDRs, second-degree relatives, and first cousins of patients who undergo colonoscopy and are found to have CRC have a significant increase in the risk of colorectal neoplasia. These data should be considered when establishing CRC screening guidelines for individuals and families.

Epidemiology and familial risk of synchronous and metachronous colorectal cancer: a population-based study in Utah.

BACKGROUND & AIMS: Patients diagnosed with colorectal cancer (CRC) are at risk for synchronous and metachronous lesions at the time of diagnosis or during follow-up evaluation. We performed a population-based study to evaluate the rate, predictors, and familial risk for synchronous and metachronous CRC in Utah. METHODS: All newly diagnosed cases of CRC between 1980 and 2010 were obtained from the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. RESULTS: Of the 18,782 patients diagnosed with CRC, 134 were diagnosed with synchronous CRC (0.71%) and 300 were diagnosed with metachronous CRC (1.60%). The risk for synchronous CRC was significantly higher in men (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.02-2.06) and in patients aged 65 years or older (OR, 1.50; 95% CI, 1.02-2.21). Synchronous CRCs were located more often in the proximal colon (OR, 1.70; 95% CI, 1.20-2.41). First-degree relatives of cases with synchronous (OR, 1.86; 95% CI, 1.37-2.53), metachronous (OR, 2.34; 95% CI, 1.62-3.36), or solitary CRC (OR, 1.75; 95% CI, 1.63-1.88) were at increased risk for developing CRC, compared with relatives of CRC-free individuals. Four percent of first-degree relatives of patients with synchronous or metachronous cancer developed CRC at younger ages than the age recommended for initiating CRC screening (based on familial risk), and therefore would not have been screened. CONCLUSIONS: Of patients diagnosed with CRC, 2.3% are found to have synchronous lesions or develop metachronous CRC during follow-up evaluation. Relatives of these patients have a greater risk of CRC than those without a family history of CRC. These results highlight the importance of obtaining a thorough family history and adhering strictly to surveillance guidelines during management of high-risk patients.

Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions.

Classification of rare missense substitutions observed during genetic testing for patient management is a considerable problem in clinical genetics. The Bayesian integrated evaluation of unclassified variants is a solution originally developed for BRCA1/2. Here, we take a step toward an analogous system for the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) that confer colon cancer susceptibility in Lynch syndrome by calibrating in silico tools to estimate prior probabilities of pathogenicity for MMR gene missense substitutions. A qualitative five-class classification system was developed and applied to 143 MMR missense variants. This identified 74 missense substitutions suitable for calibration. These substitutions were scored using six different in silico tools (Align-Grantham Variation Grantham Deviation, multivariate analysis of protein polymorphisms [MAPP], MutPred, PolyPhen-2.1, Sorting Intolerant From Tolerant, and Xvar), using curated MMR multiple sequence alignments where possible. The output from each tool was calibrated by regression against the classifications of the 74 missense substitutions; these calibrated outputs are interpretable as prior probabilities of pathogenicity. MAPP was the most accurate tool and MAPP + PolyPhen-2.1 provided the best-combined model (R(2)  = 0.62 and area under receiver operating characteristic = 0.93). The MAPP + PolyPhen-2.1 output is sufficiently predictive to feed as a continuous variable into the quantitative Bayesian integrated evaluation for clinical classification of MMR gene missense substitutions.

TRIM29 functions as a tumor suppressor in nontumorigenic breast cells and invasive ER+ breast cancer.

Tripartite motif-containing 29 (TRIM29) is a member of the TRIM protein family that has been implicated in hematologic and solid tumor cancers. We found that TRIM29 functions as a tumor suppressor in both the nontumorigenic MCF10A [estrogen receptor (ER)-/TRIM29+] breast cell line and the invasive MCF7 (ER+/TRIM29-) breast cell line. Silencing TRIM29 in MCF10A cells resulted in preneoplastic changes that included loss of polarity in three-dimensional culture, increased proliferation, anchorage-independent growth, and increased migration and invasion. Conversely, the introduction of TRIM29 into MCF7 cells caused reversion to a less aggressive phenotype by antagonizing the growth effect of 17ß-estradiol. The interaction between TRIM29 and ER signaling in MCF7 cells was supported by a reduction in ERE binding in the presence of TRIM29 and suppression of ER-dependent gene expression of TFF1, FOS, and GREB1. By microarray analyses, we showed that younger women (<55 years of age) with early-stage, ER+ breast cancer who were given no adjuvant systemic therapy had a significantly lower risk of relapse when their tumor had high TRIM29 expression (P = 0.02). This effect was not observed in older women (>55 years of age) and thus may be due to menopause and loss of circulating estrogens. Our results suggest that loss of TRIM29 expression in normal breast luminal cells can contribute to malignant transformation and lead to progression of ER+ breast cancer in premenopausal women.

Comparison of Diagnostic Sensitivity and Procedure-Related Pain of Concurrent Ultrasound-guided Fine-needle Aspiration and Core-needle Biopsy of Axillary Lymph Nodes in Patients with Suspected or Known Breast Cancer.

OBJECTIVE: Conflicting data exist on the diagnostic sensitivity of core-needle biopsy (CNB) compared to fine-needle aspiration (FNA) in the evaluation of axillary lymph node metastasis from breast cancer. Our purpose was to evaluate the sensitivity of CNB and FNA using subsequent axillary surgery as the gold standard and to compare the patients' subjective pain levels for each biopsy method. METHODS: This IRB-approved prospective study enrolled 140 patients from February 2014 to May 2019 with known or suspected breast cancer. Patients underwent both US-guided FNA and 14-gauge CNB of the same node with clip placement and rated their pain level using a verbal numerical rating scale of 0 to 10. The diagnostic sensitivities were determined by pathology of the surgically excised lymph node using the McNemar test of correlated proportions. Changes in pain scores for CNB and FNA were determined using the Wilcoxon rank sum test. RESULTS: A total of 94 patients had confirmatory excision of the biopsied node with nodal metastasis detected in 71.3% (67/94). The sensitivity of CNB for detection of nodal metastasis was 95.5% (64/67), while the sensitivity of FNA was 67.2% (45/67) (P < 0.05). Overall pain score ratings for CNB increased by 0.6 from baseline on an 11-point numerical rating scale, while overall pain score rating for FNA decreased by 0.2 from baseline (P < 0.05). CONCLUSION: Our study demonstrates that 14-gauge CNB has superior sensitivity for detection of axillary nodal metastases and mildly increased pain compared with 25-gauge FNA in patients with breast cancer.

Dosimetric Evaluation of Organs at Risk From SAVE Protocol.

PURPOSE: The objective of this work was to evaluate dosimetric characteristics to organs at risk (OARs) from short-course adjuvant vaginal cuff brachytherapy (VCB) in early endometrial cancer compared with standard of care (SOC) in a multi-institutional prospective randomized trial. METHODS AND MATERIALS: SAVE (Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care) is a prospective, phase 3, multisite randomized trial in which 108 patients requiring VCB were randomized to an experimental short-course arm (11 Gy × 2 fractions [fx] to surface) and SOC arm. Those randomized to the SOC arm were subdivided into treatment groups based on treating physician discretion as follows: 7 Gy × 3 fx to 5 mm, 5 to 5.5 Gy × 4 fx to 5 mm, and 6 Gy × 5 fx to surface. To evaluate doses to OARs of each SAVE cohort, the rectum, bladder, sigmoid, small bowel, and urethra were contoured on planning computed tomography, and doses to OARs were compared by treatment arm. Absolute doses for each OAR and from each fractionation scheme were converted to 2 Gy equivalent dose (EQD23). Each SOC arm was compared with the experimental arm separately using 1-way analysis of variance, followed by pairwise comparisons using Tukey's honestly significant difference test. RESULTS: The experimental arm had significantly lower doses for rectum, bladder, sigmoid, and urethra compared with the 7 Gy × 3 and 5 to 5.5 Gy × 4 fractionation schemes; however, the experimental arm did not differ from the 6 Gy × 5 fractionation scheme. For small bowel doses, none of the SOC fractionation schemes were statistically different than the experimental. The highest EQD23 doses to the examined OARs were observed to come from the most common dose fractionation scheme of 7 Gy × 3 fx. With a short median follow-up of 1 year, there have been no isolated vaginal recurrences. CONCLUSIONS: Experimental short-course VCB of 11 Gy × 2 fx to the surface provides a comparable biologically effective dose to SOC courses. Experimental short-course VCB was found to reduce or be comparable to D2cc and D0.1cc EQD23 doses to rectum, bladder, sigmoid, small bowel, and urethra critical structures. This may translate into a comparable or lower rate of acute and late adverse effects.

Metastasis, Mortality, and Quality of Life for Men With NCCN High and Very High Risk Localized Prostate Cancer After Surgical and/or Combined Modality Radiotherapy.

PURPOSE: To compare metastasis-free survival, overall survival, and patient-reported quality of life (QOL) of men with National Comprehensive Cancer Network high or very high risk prostate cancer after definitive surgery and/or multimodal radiotherapy (RT). PATIENTS AND METHODS: We studied a retrospective cohort study of 586 patients treated between the years 2000 and 2017 receiving radical prostatectomy with or without postoperative RT, external-beam RT (EBRT) with androgen deprivation therapy (ADT), or EBRT plus brachytherapy (Brachy) boost + ADT. Patient-reported QOL for urinary, bowel, sexual, and overall physical and mental functioning was assessed using the American Urological Association symptom scale, the Sexual Health Inventory in Men, the Rectal-Function Assessment Scale, the Expanded Prostate Cancer Index Composite, and the Veterans RAND 12-Item Health Survey. RESULTS: Median follow-up for survival was 5 years. No significant differences between the treatments were observed for overall survival or metastasis-free survival at the P < .05 threshold. The propensity-adjusted 5-year metastasis-free survival estimates for EBRT + ADT, EBRT + Brachy + ADT, and surgery were 74.6%, 94.8%, and 83.1%, respectively. The EBRT + Brachy + ADT and surgery cohorts had significantly worse mean American Urological Association symptom scores at 6 months than the EBRT + ADT cohort, which resolved by 1 year. Surgical patients had better rectal function scores than EBRT + ADT patients at years 1 to 3, but similar function thereafter. Adjuvant or salvage RT resulted in significant declines in various Expanded Prostate Cancer Index Composite urinary, sexual, and bowel domains, and Veterans RAND 12-Item Health Survey physical but not mental domains. CONCLUSION: Men with very and/or high-risk localized prostate cancer are likely to require multimodal therapy. The overall differences in survival and long-term QOL are similar for men choosing surgical versus RT pathways.

Phase I Trial of Targeted EGFR or ALK Therapy with Ipilimumab in Metastatic NSCLC with Long-Term Follow-Up.

BACKGROUND: The natural histories of, and treatment options for, epidermal growth factor receptor (EGFR)-mutated and anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancers (NSCLCs) are distinctly different from those of lung cancer that lacks actionable mutations. Ipilimumab is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor that has been approved in other malignancies. OBJECTIVE: A phase I trial of ipilimumab plus targeted therapy with either erlotinib or crizotinib was performed to assess the safety of the combination in patients with EGFR-mutated or ALK-rearranged advanced NSCLC. METHODS: Patients with EGFR-mutated or ALK-rearranged NSCLC on a stable dose of erlotinib or crizotinib for > 28 days were eligible for the study. Patients were treated with ipilimumab 3 mg/kg for four cycles plus erlotinib or crizotinib. RESULTS: Treatment of the EGFR cohort resulted in dose-limiting toxicity in three of eight patients, with grade 3 diarrhea. The protocol was amended to reduce the ipilimumab dose to 1 mg/kg. Excessive toxicity resulted in the study being closed after 14 patients. Four of 11 EGFR-mutated patients ultimately developed grade 3 colitis. Of three ALK-rearranged patients, one developed hypophysitis and another grade 2 pneumonitis. For 11 EGFR-mutated patients, progression-free survival (PFS) from the start of ipilimumab was 17.9 months. Erlotinib treatment began a median 7.7 months before ipilimumab; therefore, erlotinib PFS was 27.8 months. Median overall survival (OS) has not been reached but will be > 42.3 months from erlotinib initiation. For three ALK-rearranged patients, ipilimumab PFS was 24.1 months. Median OS has not been reached but will be at least 47.2 months from the initiation of crizotinib. CONCLUSION: Erlotinib plus ipilimumab caused excessive short-term gastrointestinal toxicity leading to early study closure. However, PFS and OS were notable; therefore, targeted therapies with immunotherapy in NSCLC merit further study. Clinicaltrials.gov registration number: NCT01998126.

Comprehensive Genomic Sequencing of Urothelial Tumors Identifies Rare SMARCB1 (INI-1)-Deficient Carcinomas of the Urinary System.

PURPOSE: Tumor genomic profiling helps direct therapy for advanced urothelial carcinoma (UC). In the course of clinical care, we encountered a patient with a complete loss of SMARCB1 (switch/sucrose nonfermentable-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1), which encodes INI-1 (integrase interactor 1), as the sole detected driver of their urinary tract tumor. Our objective was the identification and genomic characterization of urinary tract neoplasia with complete SMARCB1 loss. PATIENTS AND METHODS: Tissue from 1287 patients with UC was assayed by hybrid capture-based comprehensive genomic profiling (CGP) in the course of clinical care to evaluate genomic alterations (GA), such as, base substitutions, insertions/deletions, amplifications, copy number alterations, fusions/rearrangements, and targeted therapy opportunities. A total of 315 genes frequently altered in cancer were assayed. RESULTS: CGP identified 10 patients with SMARCB1 alterations. Of the 10 patients, 4 (1 each with renal pelvis, ureter, bladder, and unknown primary cancer) had complete loss of SMARCB1, and 6 had loss of heterozygosity with an unknown effect on function or heterozygous loss. Patients with complete SMARCB1 loss had few or no additional alterations. Compared with conventional UC, the tumor mutational burden was significantly lower (P = .004). All 4 patients with complete SMARCB1-loss tumors were < 56 years old and 3 were female. CONCLUSION: The genomic profiles of the tumors from patients with UC revealed a population of tumors driven by complete loss of SMARCB1. This previously uncharacterized subset of INI-1-deficient urinary tract tumors might constitute a new tumor category that could be sensitive to targeted therapy, including EZH2 (enhancer of zeste homolog 2) inhibition. Clinical trial testing could be challenging owing to the rarity of the disease.

Familial mortality in the Utah population database: characterizing a human aging phenotype.

We examine the effects of familial longevity and familial mortality on mortality rates for 10 leading causes of death in a Utah Population Database (UPDB) cohort. Familial excess longevity (FEL) and familial standardized mortality ratios (FSMR) were estimated for 666,921 individuals born from 1830 through 1963, who survived to at least age 40. Cox regression analysis shows that familial death and familial longevity have independent effects on cause-specific mortality rates for 10 leading causes of death. A family history of disease increases one's risk of dying from the same cause, whereas a family history of longevity is protective, except in the case of cancer. Families with greater longevity do not die of causes distinct from other members of the cohort, but they die from the same causes at reduced rates. Individuals from longer lived families have lower mortality from most age-related diseases including heart disease, stroke, and diabetes, but not cancer.

Window-of-Opportunity Study of Valproic Acid in Breast Cancer Testing a Gene Expression Biomarker.

PURPOSE: The anticancer activity of valproic acid (VPA) is attributed to the inhibition of histone deacetylase. We previously published the genomically derived sensitivity signature for VPA (GDSS-VPA), a gene expression biomarker that predicts breast cancer sensitivity to VPA in vitro and in vivo. We conducted a window-of-opportunity study that examined the tolerability of VPA and the ability of the GDSS-VPA to predict biologic changes in breast tumors after treatment with VPA. PATIENTS AND METHODS: Eligible women had untreated breast cancer with breast tumors larger than 1.5 cm. After a biopsy, women were given VPA for 7 to 12 days, increasing from 30 mg/kg/d orally divided into two doses per day to a maximum of 50 mg/kg/d. After VPA treatment, serum VPA level was measured and then breast surgery or biopsy was performed. Tumor proliferation was assessed by using Ki-67 immunohistochemistry. Histone acetylation of peripheral blood mononuclear cells was assessed by Western blot. Dynamic contrast-enhanced magnetic resonance imaging scans were performed before and after VPA treatment. RESULTS: Thirty women were evaluable. The median age was 54 years (range, 31-73 years). Fifty-two percent of women tolerated VPA at 50 mg/kg/d, but 10% missed more than two doses as a result of adverse events. Grade 3 adverse events included vomiting and diarrhea (one patient) and fatigue (one patient). The end serum VPA level correlated with a change in histone acetylation of peripheral blood mononuclear cells (ρ = 0.451; P = .024). Fifty percent of women (three of six) with triple-negative breast cancer had a Ki-67 reduction of at least 10% compared with 17% of other women. Women whose tumors had higher GDSS-VPA were more likely to have a Ki-67 decrease of at least 10% (area under the curve, 0.66). CONCLUSION: VPA was well tolerated and there was a significant correlation between serum VPA levels and histone acetylation. VPA treatment caused a decrease in proliferation of breast tumors. The genomic biomarker correlated with decreased proliferation. Inhibition of histone deacetylase is a valid strategy for drug development in triple-negative breast cancer using gene expression biomarkers.

POWERPIINC (PreOperative Window of Endocrine TheRapy Provides Information to Increase Compliance) trial: Changes in tumor proliferation index and quality of life with 7 days of preoperative tamoxifen.

OBJECTIVES: A decrease in Ki67 during neoadjuvant therapy predicts response to tamoxifen. Previous trials have shown a decreased Ki67 in breast tumors with as little as two or more weeks of preoperative tamoxifen. Shortening the preoperative treatment time in window of opportunity clinical trials makes these trials more attractive to women. POWERPIINC examined the effect of 7 days of preoperative tamoxifen on breast tumor proliferation and patient symptoms. METHODS: Women with untreated stage I/II, ER-positive, invasive breast cancer with no contraindications to tamoxifen were enrolled. Women received 20 mg of tamoxifen for 7 days up to the day of surgery. Proliferation was assessed by Ki67 immunohistochemistry before and after 7 days of tamoxifen. Symptoms and QOL were assessed by the FACT-ES and MENQOL. Adherence was measured by pill counts. RESULTS: 52 women were enrolled, and 44 were evaluable for Ki67. The median age was 58.5 years, and the median tumor diameter was 1.2 cm. Most women (73%) were post-menopausal. Most tumors were PR positive (88%) and HER2-negative (92%). The Ki67 decreased by a geometric mean of 40% (95% CI 29%-63%), and 73% (95% CI 57%-85%) of women had tumors with decreased proliferation (p = 0.0001 by paired t-test). Adherence to taking tamoxifen during the preoperative period was 100%. Women reported minimal bother from psychosocial or physical symptoms at baseline or on the day of surgery. CONCLUSION: Seven days of tamoxifen showed a similar relative decrease in Ki67 as that reported for longer courses, was acceptable to women, and could be considered for window of opportunity studies.