Patient-centered outcomes in the POLO study of active maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer.

BACKGROUND: The phase 3 POLO study demonstrated a significant progression-free survival (PFS) benefit and preserved health-related quality of life (HRQOL) for active maintenance treatment with olaparib vs placebo in patients with metastatic pancreatic cancer and a germline BRCA mutation. Here, we present a post hoc analysis of the patient-centered outcomes: time without significant symptoms of disease progression or toxicity (TWiST) and quality-adjusted TWiST (Q-TWiST). METHODS: Patients were randomized 3:2 to maintenance olaparib (300 mg tablets twice daily) or placebo. Overall survival time was divided into TWiST, toxicity (TOX; time before disease progression with significant symptoms of toxicity), and relapse (REL; time after disease progression until death or censoring). Q-TWiST was the sum of TWiST, TOX, and REL, each weighted by HRQOL utility scores during the relevant health-state period. A base-case and three sensitivity analyses were performed using differing definitions of TOX. RESULTS: In total, 154 patients were randomized (olaparib, n = 92; placebo, n = 62). TWiST was significantly longer for olaparib than placebo in the base-case analysis (14.6 vs 7.1 months; 95% CI, 2.9-12.0; p = .001) and all sensitivity analyses. No statistically significant benefit for Q-TWiST was observed in the base-case analysis (18.4 vs 15.9 months; 95% CI, -1.1 to 6.1; p = .171) or the sensitivity analyses. CONCLUSION: These results support the previous findings that maintenance olaparib significantly improves PFS relative to placebo without compromising HRQOL and demonstrate that the clinically meaningful benefits of olaparib persist even when symptoms of toxicity are considered.

Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer.

BACKGROUND: Patients with a germline BRCA1 or BRCA2 mutation make up a small subgroup of those with metastatic pancreatic cancer. The poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor olaparib has had antitumor activity in this population. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients who had a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer and disease that had not progressed during first-line platinum-based chemotherapy. Patients were randomly assigned, in a 3:2 ratio, to receive maintenance olaparib tablets (300 mg twice daily) or placebo. The primary end point was progression-free survival, which was assessed by blinded independent central review. RESULTS: Of the 3315 patients who underwent screening, 154 underwent randomization and were assigned to a trial intervention (92 to receive olaparib and 62 to receive placebo). The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval [CI], 0.35 to 0.82; P = 0.004). An interim analysis of overall survival, at a data maturity of 46%, showed no difference between the olaparib and placebo groups (median, 18.9 months vs. 18.1 months; hazard ratio for death, 0.91; 95% CI, 0.56 to 1.46; P = 0.68). There was no significant between-group difference in health-related quality of life, as indicated by the overall change from baseline in the global quality-of-life score (on a 100-point scale, with higher scores indicating better quality of life) based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (between-group difference, -2.47 points; 95% CI, -7.27 to 2.33). The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group (between-group difference, 16 percentage points; 95% CI, -0.02 to 31); 5% and 2% of the patients, respectively, discontinued the trial intervention because of an adverse event. CONCLUSIONS: Among patients with a germline BRCA mutation and metastatic pancreatic cancer, progression-free survival was longer with maintenance olaparib than with placebo. (Funded by AstraZeneca and others; POLO ClinicalTrials.gov number, NCT02184195.).

Overall Survival Results From the POLO Trial: A Phase III Study of Active Maintenance Olaparib Versus Placebo for Germline BRCA-Mutated Metastatic Pancreatic Cancer.

PURPOSE: The phase III POLO study demonstrated significant progression-free survival (PFS) benefit for active olaparib maintenance therapy versus placebo for patients with metastatic pancreatic adenocarcinoma and a germline BRCA mutation. Here, we report the final analysis of overall survival (OS) and other secondary end points. PATIENTS AND METHODS: Patients with a deleterious or suspected deleterious germline BRCA mutation whose disease had not progressed after ≥ 16 weeks of first-line platinum-based chemotherapy were randomly assigned 3:2 to active maintenance olaparib (300 mg twice daily) or placebo. The primary end point was PFS; secondary end points included OS, time to second disease progression or death, time to first and second subsequent cancer therapies or death, time to discontinuation of study treatment or death, and safety and tolerability. RESULTS: In total, 154 patients were randomly assigned (olaparib, n = 92; placebo, n = 62). No statistically significant OS benefit was observed (median 19.0 v 19.2 months; hazard ratio [HR], 0.83; 95% CI, 0.56 to 1.22; P = .3487). Kaplan-Meier OS curves separated at approximately 24 months, and the estimated 3-year survival after random assignment was 33.9% versus 17.8%, respectively. Median time to first subsequent cancer therapy or death (HR, 0.44; 95% CI, 0.30 to 0.66; P < .0001), time to second subsequent cancer therapy or death (HR, 0.61; 95% CI, 0.42 to 0.89; P = .0111), and time to discontinuation of study treatment or death (HR, 0.43; 95% CI, 0.29 to 0.63; P < .0001) significantly favored olaparib. The HR for second disease progression or death favored olaparib without reaching statistical significance (HR, 0.66; 95% CI, 0.43 to 1.02; P = .0613). Olaparib was well tolerated with no new safety signals. CONCLUSION: Although no statistically significant OS benefit was observed, the HR numerically favored olaparib, which also conferred clinically meaningful benefits including increased time off chemotherapy and long-term survival in a subset of patients.

Geographic and Ethnic Heterogeneity of Germline BRCA1 or BRCA2 Mutation Prevalence Among Patients With Metastatic Pancreatic Cancer Screened for Entry Into the POLO Trial.

PURPOSE: Germline BRCA1 and/or BRCA2 mutations (gBRCAms) are risk factors for pancreatic cancer. The extent to which demographic and geographic factors affect the uptake of gBRCAm testing in pancreatic cancer (PC) is unknown. METHODS: We conducted a retrospective, descriptive analysis of demographic/geographic data from the first 2,206 patients with metastatic PC (mPC) screened for eligibility to enter the phase III POLO trial of maintenance olaparib. No formal statistical tests were performed. RESULTS: Of 2,167 patients with previously unknown gBRCAm status, 128 (5.9%) had a newly identified gBRCAm; rates were highest in the United States, France, and Israel (9.5%, 7.6%, and 7.4%, respectively). When including patients with a previously known gBRCAm, prevalence rose to 7.2% (or 5.8% after excluding populations enriched in Ashkenazi Jews, who are known to have a high rate of BRCA1 and BRCA2 founder mutations). Patients with a gBRCAm were slightly younger (57.9 v 61.1 years) and more likely to have early-onset mPC than those without. Higher newly identified gBRCAm prevalence was observed among African American (n = 28) versus white (n = 1,808), Asian (n = 218), and other (n = 61) patients (10.7% v 6.1%, 5.0%, and 1.6%, respectively). Of 139 white patients with a gBRCAm, 110 were newly identified during screening; the majority of gBRCAms in African American, Asian, and Hispanic patients (n = 3, n = 11, and n = 5, respectively) were newly identified. CONCLUSION: We identified substantial geographic and some racial variability in gBRCAm prevalence among patients with mPC, an important consideration given the increased use of familial screening and possible future use of targeted therapies in this setting. Although our study included small numbers of nonwhite patients, prior knowledge of their gBRCAm status was limited compared with their white counterparts, which suggests disparities in genetic testing uptake.

The I1307K APC polymorphism in Ashkenazi Jews with colorectal cancer: clinical and pathologic features.

Colorectal cancer is common in Ashkenazi Jews. The I1307K APC mutation occurs in 6-7% of Ashkenazi Jews and increases the risk of colorectal cancer. This study aimed to describe the clinical, pathologic and epidemiologic features of colorectal cancer in I1307K carriers to determine whether there were any features which might warrant individual screening for the mutation. In all, 215 Ashkenazi Jews with a personal history of colorectal cancer were enrolled. Clinical and family history, pathology reports, and slides were obtained and blood drawn for I1307K determination. The presence of the mutation was determined by PCR from white blood cell DNA. Colorectal cancer pathology slides were read in a blinded fashion. Of the 215 enrolled patients, 26 (12.1%) tested positive for I1307K. There was no difference in the pathologic features between colorectal cancers in Ashkenazi carriers compared to noncarriers. There was no difference in the age at diagnosis or history of second or other primaries. Carriers had an increased likelihood of having a first-degree relative with colorectal cancer (50%) compared to noncarriers (28%, P < 0.04). We could find no distinguishing feature other than family history that characterizes I1307K positive colorectal cancers. We could find no group of Ashkenazi Jews with colorectal cancer for whom screening for I1307K would be clinically useful.

Defining the roles of aromatase inhibitors in the adjuvant treatment of early-stage breast cancer.

The widespread use of tamoxifen has led to significant improvements in survival for postmenopausal women with early-stage hormone receptor-positive breast cancer; however, approximately 30% of patients die despite receiving tamoxifen as adjuvant treatment. In addition, concerns exist regarding tamoxifen-associated side effects, including endometrial cancer and thromboembolic disease. The development of the third-generation aromatase inhibitors (AIs; anastrozole, exemestane, and letrozole) therefore represented a welcome potential alternative to tamoxifen. Several clinical trials have demonstrated the superiority of AIs over tamoxifen in the adjuvant treatment of postmenopausal women with hormone-sensitive breast cancer, but these trials differ in their design and in the characteristics of their patient populations. This review discusses the different designs of the primary adjuvant, switching, extended adjuvant, and sequencing trials that are investigating the use of AIs in the adjuvant treatment of breast cancer and provides direction regarding how the data from these trials could be used to guide treatment choice. This review also demonstrates why one should not extrapolate results from clinical trials to clinical situations that differ from the clinical trial or from clinical trials investigating a particular AI to clinical situations involving another AI.

Genetic factors and colorectal cancer in Ashkenazi Jews.

The observed increased incidence of colorectal cancer in Ashkenazi Jews compared to other populations is unexplained but likely has a genetic component. The I1307K APC polymorphism/mutation is carried by 6-8% of Ashkenazim and increases the risk of colorectal cancer 1.5-2 fold. There are few differences between the phenotype of colorectal cancer in I1307K carriers and sporadic cases. It is estimated that the mutation accounts for 6% of cases of colorectal cancer in Jews of Eastern European heritage. It should not be the subject of mass screening in Ashkenazi Jews, although it may be important in cases of familial colorectal cancer. Even rarer is the 1906G-->C MSH2 mutation carried by less than 1% of Ashkenazim, but as with other HNPCC mutations likely associated with a high risk of malignancy. Mutations at 15q13-14 are associated with the colorectal adenoma and carcinoma syndrome (CRAC) described in Ashkenazi families. The prevalence of the mutation is not known, nor its significance as a cause of colorectal cancer. Despite the paucity of genetic explanations for the high risk of colorectal cancer in Ashkenazim, that risk warrants aggressive colorectal cancer screening and particular attention to family history of malignancy in all Jews of Ashkenazi descent.

Cancer in Jews: introduction and overview.

This article is based upon a literature overview of cancer in Jews. It involves a comparison of variation in incidence and prevalence rates between Jews and non-Jews. However, the reader must exercise a certain amount of skepticism when considering secular changes in cancer incidence and prevalence and the public health implications of such cancer variation. Ashkenazi Jews have a lifetime CRC risk of 9--15%. This elevated CRC risk is similar to that of individuals in the "familial risk'' category, and differs strikingly from the 5-6% CRC risk for non-Ashkenazi members of general Western populations. A MedLine search tested the hypothesis that site-specific and/or all-cancer incidence and mortality rates are either higher or lower than expected in Ashkenazi Jews worldwide, when compared with reference populations. Results showed that all cancer incidence and mortality is not higher in Ashkenazi Jews when compared to North American non-Hispanic whites. Indeed, rates for some cancers, such as carcinoma of the lung in Ashkenazi males, are low; this example is likely attributable in large part to decreased tobacco use. Carcinoma of the ovary, pancreas, stomach, and non-Hodgkin's lymphoma have a higher incidence rate in Ashkenazi. Even though BRCA1 and BRCA2 founder mutations which predispose to carcinoma of the breast and ovary appear increased in Ashkenazi breast cancer affected women, there was no evidence supporting an elevated risk of breast cancer among Ashkenazi women. Our primary concern, however, is that Ashkenazi Jews may have one of the highest lifetime CRC risks of any ethnic group in the world, a risk that diverges significantly from that of the general population; therein, it logically calls for more intensive CRC screening guidelines. We have emphasized that the reader use caution in the interpretation of statistics which portray variation in incidence and prevalence figures for cancer in any racial, ethnic, or religious group, inclusive, of course, of Jews. Clearly, more research will be required in the interest of accuracy in the understanding of these cancer variations, since they portend the need for special cancer control strategies. A lesser degree of attention can then be given to carcinoma of the penis and uterine cervix, which occur very infrequently in Jews. We urge our colleagues to continue to probe further into these statistical differences in cancer's incidence and prevalence in order to garner a better understanding of cancer's etiology and pathogenesis.

Inflammatory bowel disease in Ashkenazi Jews: implications for familial colorectal cancer.

Inflammatory bowel disease (IBD) has a multifactorial etiology and includes ulcerative colitis (UC) and Crohn's disease (CD). Powerful epidemiologic and genetic studies have provided ample evidence that a subset of both CD and UC are attributable to a likely primary genetic etiology. This is evidenced by the recent identification of the IBD1 gene ( NOD2 ) mutations which show an association with susceptibility to CD. The IBD complex shows a significant increased frequency in Jews when compared to non-Jews. While there is an increased incidence of colorectal cancer (CRC) in patients with IBD, it nevertheless is important to realize that IBD likely accounts for no more than 1-3% of all cases of CRC in Ashkenazi Jews. Importantly, however, awareness of the increased CRC risk in IBD may aid immeasurably in preventive interventions. The molecular pathway leading to CRC in IBD appears to differ from the well-known adenoma-to-CRC sequence, given the fact that these cancers appear to arise from either flat, dysplastic tissue or dysplasia-associated lesions or masses (DALMs). An important model, but by no means an absolute one, for colon carcinogenesis in IBD follows progression from an absence of dysplasia, to indefinite dysplasia, to low-grade dysplasia, on to high-grade dysplasia, and ultimately to invasive CRC. This carcinogenic process relates to the disease duration with respect to the extent of colonic involvement and may also involve primary sclerosing cholangitis. Given this knowledge of an increased risk for CRC in UC and CD, surveillance colonoscopy should initially be performed 8-10 years after onset of symptoms as opposed to diagnosis, and it should be performed 1-2 years after 8 years of disease in patients with pancolitis or after 15 years in those with left-sided colitis. A search for dysplasia of colonic mucosa with biopsies performed in all four quadrants every 10 cm throughout the colon is exceedingly important. Additional biopsies should be taken of any flat lesions, masses, or strictures. Prophylactic colectomy may then be indicated when severe dysplasia is confirmed by knowledgeable pathologists.

Cost-effectiveness analysis of anastrozole versus tamoxifen as primary adjuvant therapy for postmenopausal women with early breast cancer: a US healthcare system perspective. The 5-year completed treatment analysis of the ATAC ('Arimidex', Tamoxifen Alone or in Combination) trial.

BACKGROUND: This study evaluated the cost-effectiveness of anastrozole versus generic tamoxifen for primary adjuvant treatment of postmenopausal women with hormone receptor-positive (HR+) early breast cancer (EBC), from a US healthcare perspective. METHODS: A probabilistic Markov model was developed using the 5-year completed treatment analysis of the ATAC ('Arimidex', Tamoxifen Alone or in Combination) trial (ISRCTN 18233230) to project outcomes for anastrozole and tamoxifen to 25 years. Resource utilization data were obtained primarily from published literature and a physician survey (including expert opinion from ATAC Steering Committee members). Drug costs were taken from published wholesale acquisition costs (anastrozole $6.56/day, generic tamoxifen $1.33/day). Other unit costs ($US 2003-4) were from standard sources. Utility estimates of relevant health states, used to compute quality-adjusted life-years (QALYs), were collected using the standard gamble technique in a cross-sectional sample of 44 patients. Costs and benefits were discounted 3% annually. RESULTS: In a cohort of 1000 postmenopausal women with HR+ EBC, the model showed anastrozole treatment (versus tamoxifen) would lead to 257 QALYs gained (0.26 QALYs gained per patient), at an additional cost of $5.21 million over 25 years ($5,212 per patient). The estimated incremental cost-effectiveness ratio (ICER) of anastrozole compared with tamoxifen was $20,246 per QALY gained ($23,541 per life-year gained). Cost-effectiveness acceptability curves indicated a >90% probability that the cost per QALY gained with anastrozole would be <$50,000. Results were robust in a sensitivity analysis. CONCLUSION: Anastrozole is a cost-effective alternative to tamoxifen for the primary adjuvant treatment of postmenopausal women with HR+ EBC.

Phase I trial of fixed dose rate infusion gemcitabine with gefitinib in patients with pancreatic carcinoma.

PURPOSE: To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of gemcitabine using a fixed dose rate infusion (FDRI) in combination with gefitinib in patients (pts) with pancreatic adenocarcinoma (PCa). PATIENTS AND METHODS: Patients with advanced PCa were given gemcitabine at the FDRI of 10 mg/m(2)/min IV on Days 1, 8, and 15 of a 28-day cycle. Dose levels of 1000, 1200, and 1500 mg/m(2) were evaluated. Oral gefitinib 250 mg was given daily. DLTs were defined as 2 instances of Grade 3 hematologic or 4 nonhematologic or any Grade 4 hematologic toxicity. At least 4 patients were treated at each dose level. Dose escalation occurred in the absence of DLTs. RESULTS: Five women and 8 men were enrolled. Median age was 59 and performance status 1. All had metastatic disease. Four patients received prior adjuvant chemoradiation for PCa, and one chemotherapy for lung cancer. Median cycles were 4 per patient. The MTD was 1,200 mg/m(2). Toxicity was predominantly hematologic. At 1,500 mg/m(2), 1 patient had Grade 4 granulocytopenia and 3 patients Grade 3 granulocytopenia. Overall, 8 patients (60 percent) developed Grade 1 or 2 acneiform rashes. One patient had Grade 3 vomiting; no significant diarrhea or liver toxicity was seen. There were no objective responses seen. Median time to progression and overall survival were 4.57 months and 7.13 months, respectively. CONCLUSION: Combining FDRI gemcitabine with gefitinib is feasible and tolerable. The recommended dose of gemcitabine is 1,200 mg/m(2) when used with gefitinib 250 mg daily.

Oxaliplatin-related acute myelogenous leukemia.

A 56-year-old woman diagnosed with a poorly differentiated cecal adenocarcinoma with metastases to ovaries, omentum, and sigmoid colon went into remission after 12 cycles of infusional 5-fluorouracil, luecovorin, and oxaliplatin (FOLFOX-4 regimen). Thirteen months later, a pelvic recurrence was diagnosed, and the patient received nine cycles of FOLFOX-6 plus bevacizumab, resulting in a clinical complete response but the development of pancytopenia. Bone marrow biopsy was consistent with therapy-related acute myelogenous leukemia. Chromosome analysis showed structural rearrangements with partial deletions of the long arms of chromosomes 5, 7, 20, and 21, as well as trisomy of chromosome 8 and losses of chromosomes 3 and 11. Induction chemotherapy led to remission, but the patient died two months later from complications of colon cancer progression. It is likely that the leukemia was related to the oxaliplatin administration.

ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer.

PURPOSE: To update the recommendations for the use of tumor marker tests in the prevention, screening, treatment, and surveillance of gastrointestinal cancers. METHODS: For the 2006 update, an update committee composed of members from the full Panel was formed to complete the review and analysis of data published since 1999. Computerized literature searches of Medline and the Cochrane Collaboration Library were performed. The Update Committee's literature review focused attention on available systematic reviews and meta-analyses of published tumor marker studies. RECOMMENDATIONS AND CONCLUSION: For colorectal cancer, it is recommended that carcinoembryonic antigen (CEA) be ordered preoperatively, if it would assist in staging and surgical planning. Postoperative CEA levels should be performed every 3 months for stage II and III disease for at least 3 years if the patient is a potential candidate for surgery or chemotherapy of metastatic disease. CEA is the marker of choice for monitoring the response of metastatic disease to systemic therapy. Data are insufficient to recommend the routine use of p53, ras, thymidine synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, microsatellite instability, 18q loss of heterozygosity, or deleted in colon cancer (DCC) protein in the management of patients with colorectal cancer. For pancreatic cancer, CA 19-9 can be measured every 1 to 3 months for patients with locally advanced or metastatic disease receiving active therapy. Elevations in serial CA 19-9 determinations suggest progressive disease but confirmation with other studies should be sought. New markers and new evidence to support the use of the currently reviewed markers will be evaluated in future updates of these guidelines.

Breast surgery in the 'Arimidex, Tamoxifen Alone or in Combination' (ATAC) trial: American women are more likely than women from the United Kingdom to undergo mastectomy.

BACKGROUND: Various factors affect patients' decisions regarding whether to undergo surgery for the treatment of early-stage breast carcinoma. The 'Arimidex, Tamoxifen Alone or in Combination' (ATAC) trial, the largest multinational randomized trial of adjuvant therapy for patients with operable breast carcinoma to date, offers the opportunity to investigate whether nationality is one such factor. METHODS: After receiving primary therapy for early-stage breast carcinoma, 9,366 women (from a total of 21 countries) were randomized to receive anastrozole, tamoxifen, or anastrozole plus tamoxifen for 5 years. In the current study, mastectomy and breast conservation rates were compared among participating countries. The possibility that variations from country to country could be explained by inequalities in terms of pathologic, clinical, and hospital-related correlates of surgical choice was explored first on univariate analysis and then on multivariate logistic analysis. RESULTS: National mastectomy rates ranged from 20% to 97%; 51% of the 2,222 enrollees from the United States had undergone mastectomy, compared with 42% of the 3228 enrollees from the United Kingdom (odds ratio [OR], 1.43; 95% confidence interval [CI], 1.28-1.60; P < 0.001). On univariate analysis, larger tumor size, positive lymph node status, higher tumor grade, older age, and adjuvant chemotherapy use were found to be correlated with mastectomy use. In contrast, positive hormone receptor status, increased body weight, and enrollment at a center that had more than 40 enrollees were found to be associated with breast conservation. The same correlates were identified on multivariate logistic analysis (P < 0.05), except that the number of enrollees at a patient's treatment center no longer possessed predictive value. After correction for these correlated factors, residence in the United States (compared with residence in the United Kingdom) remained an independent predictor of mastectomy use (OR, 1.44; 95% CI, 1.26-1.64; P < 0.001). CONCLUSIONS: American women enrolled in the ATAC trial were more likely to undergo aggressive surgery compared with their counterparts from the United Kingdom. More generally, nationality was found to be an independent determinant of surgical choice in the current study.