Mutational Landscapes of Smoking-Related Cancers in Caucasians and African Americans: Precision Oncology Perspectives at Wake Forest Baptist Comprehensive Cancer Center.

Background: Cancers related to tobacco use and African-American ancestry are under-characterized by genomics. This gap in precision oncology research represents a major challenge in the health disparities in the United States. Methods: The Precision Oncology trial at the Wake Forest Baptist Comprehensive Cancer Center enrolled 431 cancer patients from March 2015 to May 2016. The composition of these patients consists of a high representation of tobacco-related cancers (e.g., lung, colorectal, and bladder) and African-American ancestry (13.5%). Tumors were sequenced to identify mutations to gain insight into genetic alterations associated with smoking and/or African-American ancestry. Results: Tobacco-related cancers exhibit a high mutational load. These tumors are characterized by high-frequency mutations in TP53, DNA damage repair genes (BRCA2 and ATM), and chromatin remodeling genes (the lysine methyltransferases KMT2D or MLL2, and KMT2C or MLL3). These tobacco-related cancers also exhibit augmented tumor heterogeneities. Smoking related genetic mutations were validated by The Cancer Genome Atlas dataset that includes 2,821 cases with known smoking status. The Wake Forest and The Cancer Genome Atlas cohorts (431 and 7,991 cases, respectively) revealed a significantly increased mutation rate in the TP53 gene in the African-American subgroup studied. Both cohorts also revealed 5 genes (e.g. CDK8) significantly amplified in the African-American population. Conclusions: These results provide strong evidence that tobacco is a major cause of genomic instability and heterogeneity in cancer. TP53 mutations and key oncogene amplifications emerge as key factors contributing to cancer outcome disparities among different racial/ethnic groups.

Circulating mutational portrait of cancer: manifestation of aggressive clonal events in both early and late stages.

BACKGROUND: Solid tumors residing in tissues and organs leave footprints in circulation through circulating tumor cells (CTCs) and circulating tumor DNAs (ctDNA). Characterization of the ctDNA portraits and comparison with tumor DNA mutational portraits may reveal clinically actionable information on solid tumors that is traditionally achieved through more invasive approaches. METHODS: We isolated ctDNAs from plasma of patients of 103 lung cancer and 74 other solid tumors of different tissue origins. Deep sequencing using the Guardant360 test was performed to identify mutations in 73 clinically actionable genes, and the results were associated with clinical characteristics of the patient. The mutation profiles of 37 lung cancer cases with paired ctDNA and tumor genomic DNA sequencing were used to evaluate clonal representation of tumor in circulation. Five lung cancer cases with longitudinal ctDNA sampling were monitored for cancer progression or response to treatments. RESULTS: Mutations in TP53, EGFR, and KRAS genes are most prevalent in our cohort. Mutation rates of ctDNA are similar in early (I and II) and late stage (III and IV) cancers. Mutation in DNA repair genes BRCA1, BRCA2, and ATM are found in 18.1% (32/177) of cases. Patients with higher mutation rates had significantly higher mortality rates. Lung cancer of never smokers exhibited significantly higher ctDNA mutation rates as well as higher EGFR and ERBB2 mutations than ever smokers. Comparative analysis of ctDNA and tumor DNA mutation data from the same patients showed that key driver mutations could be detected in plasma even when they were present at a minor clonal population in the tumor. Mutations of key genes found in the tumor tissue could remain in circulation even after frontline radiotherapy and chemotherapy suggesting these mutations represented resistance mechanisms. Longitudinal sampling of five lung cancer cases showed distinct changes in ctDNA mutation portraits that are consistent with cancer progression or response to EGFR drug treatment. CONCLUSIONS: This study demonstrates that ctDNA mutation rates in the key tumor-associated genes are clinical parameters relevant to smoking status and mortality. Mutations in ctDNA may serve as an early detection tool for cancer. This study quantitatively confirms the hypothesis that ctDNAs in circulation is the result of dissemination of aggressive tumor clones and survival of resistant clones. This study supports the use of ctDNA profiling as a less-invasive approach to monitor cancer progression and selection of appropriate drugs during cancer evolution.

Incidence and clinical significance of ESR1 mutations in heavily pretreated metastatic breast cancer patients.

BACKGROUND: ESR1 mutation has recently emerged as one of the important mechanisms involved in endocrine resistance. The incidence and clinical implication of ESR1 mutation has not been well evaluated in heavily pretreated breast cancer patients. METHODS: We conducted a retrospective review of advanced breast cancer patients with tumors who underwent next-generation sequencing genomic profiling using Foundation One test at Cancer Treatment Centers of America(®) regional hospitals between November 2012 and November 2014. RESULTS: We identified a total of 341 patients including 217 (59%) estrogen receptor (ER)+, 177 (48%) progesterone receptor (PR)+, 30 (8%) hormone receptor+/HER2 positive, and 119 (32%) triple negative patients. ESR1 mutation was noted in 27/222 (12.1%) ER+ or PR+ breast cancer patients. All ER+ patients received at least one line of an aromatase inhibitor. All 28 patients were found to harbor ESR1 mutations affecting ligand-binding domain with the most common mutations affecting Y537 (17/28, 60.7%) and D538 (9/28, 32.1%). In this cohort, 19 (67.9%) patients carried three or more, seven (25%) patients had one or two additional genomic alterations and one (3.6%) patient had an ESR1 mutation only. Of 28 patients, three patients were treated with fulvestrant immediately before and two patients were treated after next-generation sequencing testing; only one patient achieved stable disease for 8 months and the other four patients had progression of disease. In all, 3/3 (100%) patients before testing and 2/4 (50%) after testing treated with exemestane and everolimus achieved stable disease for at least 6 months. CONCLUSION: ESR1 mutation was found in 12.1% of a large cohort of advanced breast cancer patients. Exemestane in combination with everolimus might be a reasonable option. Prospective studies are warranted to validate these findings.

Initial experience with genomic profiling of heavily pretreated breast cancers.

BACKGROUND: Rapidly evolving advances in the understanding of theorized unique driver mutations within individual patient's cancers, as well as dramatic reduction in the cost of genomic profiling, have stimulated major interest in the role of such testing in routine clinical practice. The aim of this study was to report our initial experience with genomic testing in heavily pretreated breast cancer patients. METHODS: Patients with primary or recurrent breast cancer managed at any of our five hospitals and whose malignancy had failed to respond to therapy or had progressed on all recognized standard-of-care options were offered the opportunity to have their cancer undergo next-generation sequencing genomic profiling. RESULTS: Of a total of 101 patients, 98 (97 %) had at least one specific genomic alteration identified. A total of 465 different somatic genetic abnormalities were revealed in this group of patients. Although 52 % of patients were found to have an abnormality for which an U.S. Food and Drug Administration (FDA)-approved drug was available, 69 % of patients had an FDA-approved agent for an indication other than breast cancer. The most common genomic alterations of potential clinical consequence were PIK3 (25 %), FGFR1 (16 %), AKT (11 %), PTEN (10 %), ERBB2 (8 %), JAK2 (6 %), and RAF1 (5 %). CONCLUSIONS: Almost all advanced breast cancers possess at least one well-characterized genomic alteration that might be actionable at the clinical level. Further, in most cases, a plausible argument can be advanced for the potential biological and clinical relevance of an FDA-approved antineoplastic agent not currently indicated in the treatment of breast cancer.

Prognostic value of changes in quality of life scores in prostate cancer.

BACKGROUND: Several studies in the oncology literature have demonstrated the prognostic value of baseline quality of life (QoL). We investigated whether changes in QoL could predict survival in prostate cancer patients. METHODS: We evaluated 250 prostate cancer patients treated at our institution between Jan 2001 and Dec 2009 who were available for a minimum follow-up of 3 months. QoL was evaluated at baseline and after 3 months of treatment initiation using EORTC-QLQ-C30. Cox regression evaluated the prognostic significance of baseline and changes in QoL scores after adjusting for relevant clinical and demographic variables. RESULTS: Median overall survival was 89.1 months (95% CI: 56.5-121.7). Baseline QoL scale predictive of survival upon multivariate analysis was fatigue (p = 0.001). Associations between changes in QoL and survival, upon multivariate analysis, were observed for dyspnea and cognitive functioning. Every 10-point increase (worsening) in dyspnea was associated with a 16% increased risk of death (HR = 1.16; 95% CI = 1.02 to 1.30, p = 0.02), and every 10-point increase (improvement) in cognitive functioning was associated with a 24% decreased risk of death (HR = 0.76; 95% CI = 0.54 to 0.98, p = 0.04). CONCLUSIONS: This study provides preliminary evidence to indicate that prostate cancer patients with better baseline fatigue and patients whose dyspnea and cognitive functioning improves within 3 months of treatment are at a significantly decreased risk of mortality.

Longitudinal health-related quality of life assessment: implications for prognosis in ovarian cancer.

BACKGROUND: There is no information in the literature on the impact of changes in quality of life (QoL) scores on prognosis in ovarian cancer. We investigated whether changes in QoL during treatment could predict survival in ovarian cancer patients. METHODS: We evaluated 137 ovarian cancer patients treated at our institution between Jan 2001 and Dec 2009 who were available for a minimum follow-up of 3 months. QoL was evaluated at baseline and after 3 months of treatment using EORTC-QLQ-C30. Cox regression evaluated the prognostic significance of baseline and changes in QoL scores after adjusting for clinical and demographic variables. RESULTS: Associations between changes in QoL and survival were observed for global function, appetite loss and constipation. Every 10-point increase (improvement) in global function from baseline to 3 months was associated with a 10% decreased risk of death (HR=0.90; 95% CI: 0.81 to 0.99, p=0.03). The corresponding HRs for 10-point increase (deterioration) in appetite loss and constipation scales were 1.20 (95% CI: 1.06 to 1.35; p=0.005) and 1.13 (95% CI: 1.02 to 1.24; p=0.02) respectively. CONCLUSIONS: This exploratory study provides evidence that an improvement in appetite, constipation and global health scores during the first 3 months of treatment is significantly associated with improved survival time in ovarian cancer. These findings justify serial, systematic assessment of global health, appetite and constipation in ovarian cancer patients being treated, and suggest that modalities designed to improve these functions may be beneficial clinically.

Effect of naturopathic and nutritional supplement treatment on tumor response, control, and recurrence in patients with prostate cancer treated with radiation therapy.

OBJECTIVES: Use of naturopathic and nutritional supplements (NNS) with antioxidant activity is controversial in patients receiving radiation therapy. The effects of concomitant use of NNS with antioxidant activity during radiation therapy for prostate cancer were investigated in terms of clinical tumor responsiveness, kinetics, and durability. MATERIALS AND METHODS: A retrospective investigation was done of 134 patients treated with curative intent for limited-stage prostate cancer by radiation therapy. Patients self-selected to receive NNS as part of their treatment and maintenance during an extended post-treatment interval of at least 2 years. The outcome measures were the following: prostate-specific antigen (PSA) nadir; ≥24 months post-treatment PSA; time to reach nadir; and time to last follow-up were compared across +NNS and -NNS. RESULTS: Sixty-nine (69) patients elected to receive NNS while 65 did not. Seventy-seven (77) (+NNS 39, -NNS 38) patients received hormone therapy while 57 (+NNS 30, -NNS 27) did not. In the nonhormone cohort, median pretreatment PSA, nadir, post-treatment PSA, time to reach nadir, and time to follow-up were 5.5 ng/mL, 0.56 ng/mL, 0.61 ng/mL, 25 months, and 39.7 months for the -NNS group and 5.1 ng/mL, 0.32 ng/mL, 0.44 ng/mL, 27 months, and 50.1 months for the +NNS group, respectively (p>0.05 for all). Similarly, no significant differences were observed between +NNS and -NNS in the hormone-receiving cohort. CONCLUSIONS: The clinical tumor response to radiation therapy in patients with limited-stage prostate cancer is not inhibited by concomitant NNS based on the magnitude of the PSA response, the velocity of the PSA nadir, and the duration of PSA normalization.

Longitudinal health-related quality of life assessment implications for prognosis in stage IV pancreatic cancer.

OBJECTIVES: We investigated whether changes in quality of life (QoL) during treatment could predict survival in stage IV pancreatic cancer. METHODS: Quality of life was evaluated at baseline and after 3 months of treatment using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) in 186 patients with stage IV pancreatic cancer. Cox regression evaluated the prognostic significance of baseline and changes in QoL scores after adjusting for age, sex, and treatment history. RESULTS: One hundred twenty-one patients were males and 65 were females. One hundred twenty-seven patients' condition was newly diagnosed, whereas 59 were previously treated. The mean age at diagnosis was 55.1 years. Baseline QoL scale predictive of survival upon multivariate analysis was global health (hazard ratio, 0.88; 95% confidence interval, 0.81-0.95; P = 0.001). On multivariate analysis, QoL change variable that was significantly predictive of survival after 3 months of treatment was cognitive function (hazard ratio, 0.89; 95% confidence interval, 0.79-0.99; P = 0.04). CONCLUSIONS: This study provides preliminary evidence to indicate that patients with stage IV pancreatic cancer who have a better global health at baseline as well as those whose cognitive function improves within 3 months of treatment have a significantly increased probability of survival.

Predicting survival in prostate cancer: the role of quality of life assessment.

PURPOSE: While the use of quality of life (QoL) assessment has been increasing in clinical oncology, few studies have examined its prognostic significance in prostate cancer. We investigated the association between QoL at presentation and survival in prostate cancer. METHODS: We retrospectively reviewed 673 patients treated at two single-system cancer centers between January 2001 and December 2008. QoL was evaluated using EORTC-QLQ-C30. Patient survival was defined as the time interval between the date of first patient visit and the date of death/date of last contact. Univariate and multivariate Cox regression was performed to evaluate the prognostic significance of QoL. RESULTS: Mean age at presentation was 63.2 years. Patient stage of disease at diagnosis was I, 4; II, 464; III, 76; IV, 107; and 22 indeterminate. Median overall survival was 89.1 months (95% CI: 46.1-132.0). QoL scales predictive of survival upon univariate analysis were physical, role, emotional, social, fatigue, nausea/vomiting, pain, dyspnea, insomnia, loss of appetite, and constipation (p < 0.01 for all). Multivariate analyses found fatigue (p = 0.02) and constipation (p = 0.01) to be significantly associated with survival. CONCLUSIONS: Baseline QoL provides useful prognostic information in prostate cancer. These findings have important implications for patient stratification in clinical trials and may aid decision making in clinical practice.

The prognostic role of quality of life assessment in breast cancer.

While the use of quality of life (QoL) assessments has been increasing in oncology, few studies have examined the prognostic significance of QoL in breast cancer. We investigated the association between QoL at presentation and survival in breast cancer. We examined 1,511 breast cancer patients treated at two single-system cancer centers between January 2001 and December 2008. QoL was evaluated using the validated survey instrument EORTC-QLQ-C30. Patient survival was defined as the time interval between the date of first patient visit and the date of death from any cause/date of last contact. Univariate and multivariate Cox regression analyses were performed to evaluate the prognostic significance of QoL after controlling for the effects of age, tumor stage, and prior treatment history. Mean age at presentation was 52.5 years. There were 590 analytic and 921 non-analytic patients. Patient stage of disease at diagnosis was I, 335; II, 591; III, 290; IV, 159; and 136 indeterminate. Median overall survival was 32.8 months (95% CI: 27.6-38.0). On univariate analysis, QoL function and symptom scales that were predictive of survival were physical (p < 0.001), role (p < 0.001), cognitive (p = 0.003), social (p < 0.001), fatigue (p < 0.001), nausea/vomiting (p < 0.001), pain (p < 0.001), dyspnea (p < 0.001), loss of appetite (p < 0.001), and constipation (p < 0.001). On multivariate analyses, only role function (degree of impairment of work and/or leisure/hobby related activities) was significantly associated with survival. This study suggests that baseline QoL (in particular, the role function) provides useful prognostic information in breast cancer.

Quality of life assessment as a predictor of survival in non-small cell lung cancer.

BACKGROUND: There are conflicting and inconsistent results in the literature on the prognostic role of quality of life (QoL) in cancer. We investigated whether QoL at admission could predict survival in lung cancer patients. METHODS: The study population consisted of 1194 non-small cell lung cancer patients treated at our institution between Jan 2001 and Dec 2008. QoL was evaluated using EORTC-QLQ-C30 prior to initiation of treatment. Patient survival was defined as the time interval between the date of first patient visit and the date of death from any cause/date of last contact. Univariate and multivariate Cox regression evaluated the prognostic significance of QoL. RESULTS: Mean age at presentation was 58.3 years. There were 605 newly diagnosed and 589 previously treated patients; 601 males and 593 females. Stage of disease at diagnosis was I, 100; II, 63; III, 348; IV, 656; and 27 indeterminate. Upon multivariate analyses, global QoL as well as physical function predicted patient survival in the entire study population. Every 10-point increase in physical function was associated with a 10% increase in survival (95% CI = 6% to 14%, p < 0.001). Similarly, every 10-point increase in global QoL was associated with a 9% increase in survival (95% CI = 6% to 11%, p < 0.001). Furthermore, physical function, nausea/vomiting, insomnia, and diarrhea (p < 0.05 for all) in newly diagnosed patients, but only physical function (p < 0.001) in previously treated patients were predictive of survival. CONCLUSIONS: Baseline global QoL and physical function provide useful prognostic information in non-small cell lung cancer patients.

Can changes in health related quality of life scores predict survival in stages III and IV colorectal cancer?

BACKGROUND: Several studies have demonstrated the predictive significance on survival of baseline quality of life (QoL) in colorectal cancer (CRC) with little information on the impact of changes in QoL scores on prognosis in CRC. We investigated whether changes in QoL during treatment could predict survival in CRC. METHODS: We evaluated 396 stages III-IV CRC patients available for a minimum follow-up of 3 months. QoL was evaluated at baseline and after 3 months of treatment using EORTC QLQ-C30. Cox regression evaluated the prognostic significance of baseline, 3-month and changes in QoL scores after adjusting for age, gender and stage at diagnosis. RESULTS: After adjusting for covariates, every 10-point increase in both baseline appetite loss and global QoL score was associated with a 7% increased risk of death with HR = 1.07 (95% CI, 1.01-1.14; P = 0.02) and (HR = 0.93 (95% CI, 0.87-0.98; P = 0.01) respectively. A lower risk of death was associated with a 10-point improvement in physical function at 3 months (HR, 0.86; 95% CI, 0.78-0.94; P = 0.001). Surprisingly, a higher risk of death was associated with a 10-point improvement in social function at 3 months (HR, 1.08; 95% CI, 1.02-1.13; P = 0.008). CONCLUSIONS: This study provides preliminary evidence to indicate that CRC patients whose physical function improves within 3 months of treatment have a significantly increased probability of survival. These findings should be used in clinical practice to systematically address QoL-related problems of CRC patients throughout their treatment course.

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Percutaneous radiofrequency-assisted excision of fibroadenomas.

INTRODUCTION: Fibroadenomas are a frequently encountered benign tumor that will occur in approximately 10% of women during their lifetime. Although the natural history would suggest fibroadenomas diagnosed with minimally invasive needle core biopsy can be safely observed, the majority are still surgically removed in the operating room. In an effort to limit the more than 500,000 surgical fibroadenoma removals performed each year, percutaneous excision has become a viable alternative. Percutaneous excision of intact fibroadenomas versus removal with a multiple core sampling technique has the dual potential advantage of causing minimal intervention combined with provision of adequate sample for thorough histopathology and margin analysis for confirmation of complete removal. An 18-month retrospective analysis was undertaken to evaluate the utilization of a new radiofrequency-assisted biopsy device in the successful removal and continued absence of histologically confirmed fibroadenomas on 4- to 6-month follow-up imaging. METHODS: Between April 2004 and November 2005, 100 patients underwent ultrasound- or stereotactic-guided, radiofrequency-assisted intact percutaneous excision of 106 diagnosed fibroadenomas of the breast. Patients were comprised of 100 women whose ages ranged from 18-70 years (median age, 45 years). RESULTS: Indications for the procedure included palpable mass, 77; abnormal mammogram, 13; and abnormal ultrasound, 10, as the patient's initial presentation. Ultrasound was used to guide the procedure in 82 patients, and stereotactic was used in 18 patients. One early study procedure was performed under general anesthesia; the remaining studies were performed under local anesthesia (1% lidocaine) using from 10 to 45 mL. On pathologic examination, the tumors ranged in size from 6 to 27 mm (mean diameter, 14 mm) and weighed from 0.6 to 2.0 g (mean weight, 1.0 g). Patients reported minimum discomfort related to the procedure; pain scores ranged from 0 to 10 (mean pain score, <1). Complications were minimal, with only 2 patients having bleeding, which was controlled by conservative measures. At the 4- to 6-month follow-up, 79 of 85 (93%) evaluable patients showed no physical or imaging evidence of residual fibroadenoma, an additional 5 patients have reported no physical findings or further complaints and have required no further need for medical evaluation, 8 have been lost to follow-up, and 2 have yet to be reevaluated. CONCLUSIONS: Percutaneous ultrasound- or stereotactic-guided, radiofrequency-assisted excision of fibroadenomas of the breast may be performed in an ambulatory setting under local anesthesia. The procedure provides intact specimens that in most cases appear to be completely removed after follow-up of 4 to 6 months. The procedure is well tolerated by patients and is associated with minimal complications.