Case Report: Response to ipilimumab and nivolumab in a patient with adrenocortical carcinoma.

Background: Adrenocortical carcinoma (ACC) is a rare malignancy with limited treatment options. The evidence for the use of immunotherapy in ACC has been conflicting, with overall response rates ranging from 6 - 33%. Case presentation: We describe the case of a 32 year old patient who was initially thought to have an inoperable clear cell renal cell carcinoma and was treated with immunotherapy with ipilimumab and nivolumab. The patient had an excellent partial response to treatment. Further work-up prior to consideration of surgery demonstrated that the tumour was an ACC, rather than a renal cancer. She had a right adrenalectomy and right hepatectomy, achieving an R0 resection and remains disease-free one year after surgery. Conclusion: This case illustrates the challenge of diagnosing ACC, and that doublet immunotherapy with ipilimumab and nivolumab can have significant clinical efficacy in ACC.

Detecting and Tracking Circulating Tumour DNA Copy Number Profiles during First Line Chemotherapy in Oesophagogastric Adenocarcinoma.

DNA somatic copy number aberrations (SCNAs) are key drivers in oesophagogastric adenocarcinoma (OGA). Whether minimally invasive SCNA analysis of circulating tumour (ct)DNA can predict treatment outcomes and reveal how SCNAs evolve during chemotherapy is unknown. We investigated this by low-coverage whole genome sequencing (lcWGS) of ctDNA from 30 patients with advanced OGA prior to first-line chemotherapy and on progression. SCNA profiles were detectable pretreatment in 23/30 (76.7%) patients. The presence of liver metastases, primary tumour in situ, or of oesophageal or junctional tumour location predicted for a high ctDNA fraction. A low ctDNA concentration associated with significantly longer overall survival. Neither chromosomal instability metrics nor ploidy correlated with chemotherapy outcome. Chromosome 2q and 8p gains before treatment were associated with chemotherapy responses. lcWGS identified all amplifications found by prior targeted tumour tissue sequencing in cases with detectable ctDNA as well as finding additional changes. SCNA profiles changed during chemotherapy, indicating that cancer cell populations evolved during treatment; however, no recurrent SCNA changes were acquired at progression. Tracking the evolution of OGA cancer cell populations in ctDNA is feasible during chemotherapy. The observation of genetic evolution warrants investigation in larger series and with higher resolution techniques to reveal potential genetic predictors of response and drivers of chemotherapy resistance. The presence of liver metastasis is a potential biomarker for the selection of patients with high ctDNA content for such studies.

Neoadjuvant FOLFIRINOX in Patients With Borderline Resectable Pancreatic Cancer: A Systematic Review and Patient-Level Meta-Analysis.

BACKGROUND: FOLFIRINOX is a standard treatment for metastatic pancreatic cancer patients. The effectiveness of neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer (BRPC) remains debated. METHODS: We performed a systematic review and patient-level meta-analysis on neoadjuvant FOLFIRINOX in patients with BRPC. Studies with BRPC patients who received FOLFIRINOX as first-line neoadjuvant treatment were included. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival, resection rate, R0 resection rate, and grade III-IV adverse events. Patient-level survival outcomes were obtained from authors of the included studies and analyzed using the Kaplan-Meier method. RESULTS: We included 24 studies (8 prospective, 16 retrospective), comprising 313 (38.1%) BRPC patients treated with FOLFIRINOX. Most studies (n = 20) presented intention-to-treat results. The median number of administered neoadjuvant FOLFIRINOX cycles ranged from 4 to 9. The resection rate was 67.8% (95% confidence interval [CI] = 60.1% to 74.6%), and the R0-resection rate was 83.9% (95% CI = 76.8% to 89.1%). The median OS varied from 11.0 to 34.2 months across studies. Patient-level survival data were obtained for 20 studies representing 283 BRPC patients. The patient-level median OS was 22.2 months (95% CI = 18.8 to 25.6 months), and patient-level median progression-free survival was 18.0 months (95% CI = 14.5 to 21.5 months). Pooled event rates for grade III-IV adverse events were highest for neutropenia (17.5 per 100 patients, 95% CI = 10.3% to 28.3%), diarrhea (11.1 per 100 patients, 95% CI = 8.6 to 14.3), and fatigue (10.8 per 100 patients, 95% CI = 8.1 to 14.2). No deaths were attributed to FOLFIRINOX. CONCLUSIONS: This patient-level meta-analysis of BRPC patients treated with neoadjuvant FOLFIRINOX showed a favorable median OS, resection rate, and R0-resection rate. These results need to be assessed in a randomized trial.

Ultra-Sensitive Mutation Detection and Genome-Wide DNA Copy Number Reconstruction by Error-Corrected Circulating Tumor DNA Sequencing.

BACKGROUND: Circulating free DNA sequencing (cfDNA-Seq) can portray cancer genome landscapes, but highly sensitive and specific technologies are necessary to accurately detect mutations with often low variant frequencies. METHODS: We developed a customizable hybrid-capture cfDNA-Seq technology using off-the-shelf molecular barcodes and a novel duplex DNA molecule identification tool for enhanced error correction. RESULTS: Modeling based on cfDNA yields from 58 patients showed that this technology, requiring 25 ng of cfDNA, could be applied to >95% of patients with metastatic colorectal cancer (mCRC). cfDNA-Seq of a 32-gene, 163.3-kbp target region detected 100% of single-nucleotide variants, with 0.15% variant frequency in spike-in experiments. Molecular barcode error correction reduced false-positive mutation calls by 97.5%. In 28 consecutively analyzed patients with mCRC, 80 out of 91 mutations previously detected by tumor tissue sequencing were called in the cfDNA. Call rates were similar for point mutations and indels. cfDNA-Seq identified typical mCRC driver mutations in patients in whom biopsy sequencing had failed or did not include key mCRC driver genes. Mutations only called in cfDNA but undetectable in matched biopsies included a subclonal resistance driver mutation to anti-EGFR antibodies in KRAS, parallel evolution of multiple PIK3CA mutations in 2 cases, and TP53 mutations originating from clonal hematopoiesis. Furthermore, cfDNA-Seq off-target read analysis allowed simultaneous genome-wide copy number profile reconstruction in 20 of 28 cases. Copy number profiles were validated by low-coverage whole-genome sequencing. CONCLUSIONS: This error-corrected, ultradeep cfDNA-Seq technology with a customizable target region and publicly available bioinformatics tools enables broad insights into cancer genomes and evolution. CLINICALTRIALSGOV IDENTIFIER: NCT02112357.

Patient-derived organoids model treatment response of metastatic gastrointestinal cancers.

Patient-derived organoids (PDOs) have recently emerged as robust preclinical models; however, their potential to predict clinical outcomes in patients has remained unclear. We report on a living biobank of PDOs from metastatic, heavily pretreated colorectal and gastroesophageal cancer patients recruited in phase 1/2 clinical trials. Phenotypic and genotypic profiling of PDOs showed a high degree of similarity to the original patient tumors. Molecular profiling of tumor organoids was matched to drug-screening results, suggesting that PDOs could complement existing approaches in defining cancer vulnerabilities and improving treatment responses. We compared responses to anticancer agents ex vivo in organoids and PDO-based orthotopic mouse tumor xenograft models with the responses of the patients in clinical trials. Our data suggest that PDOs can recapitulate patient responses in the clinic and could be implemented in personalized medicine programs.

Attitudes of Patients With Gastrointestinal Cancers Toward Research Biopsies.

BACKGROUND: Research biopsies are an increasingly important component of clinical trials, but there are concerns that biopsies may deter patients from participating in research. PATIENTS AND METHODS: Patients participating in a single-center study investigating the feasibility of molecular profiling in advanced gastrointestinal cancers were asked to complete a questionnaire regarding their reasons for consenting/declining optional research biopsies and blood samples. These samples were mainly for exploratory translational research and were unlikely to influence patients' treatment. RESULTS: One hundred ninety-six (88%) of the 222 patients registered in the study completed the questionnaire. One hundred twenty-six patients (64%) stated they consented to a biopsy and 180 patients (92%) to blood sample collection. Male patients (P = .033) and patients with a good performance status (PS) were more willing to consent to a biopsy (79% for PS 0, 63% for PS 1, 43% for PS 2; P = .012). Eighty-eight patients (70%) who consented to a biopsy gave an altruistic reason (eg, to help research and/or others) as a reason why they consented. Only 8 patients (6%) consented solely because they believed it might influence their treatment. Reasons for declining biopsies included a wish to avoid additional procedures (n = 18; 29%) and previous unpleasant biopsy experiences (n = 9; 15%). CONCLUSION: Many patients with advanced gastrointestinal cancer appear willing to undergo biopsies for exploratory research purposes. In our study, patients who consented to a biopsy mainly did so for altruistic reasons and/or a wish to contribute to scientific research.

FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis.

BACKGROUND: 35% of patients with pancreatic cancer have unresectable locally advanced disease at diagnosis. Several studies have examined systemic chemotherapy with FOLFIRINOX (leucovorin and fluorouracil plus irinotecan and oxaliplatin) in patients with locally advanced pancreatic cancer. We aimed to assess the effectiveness of FOLFIRINOX as first-line treatment in this patient population. METHODS: We systematically searched Embase, MEDLINE (OvidSP), Web of Science, Scopus, PubMed Publisher, Cochrane, and Google Scholar from July 1, 1994, to July 2, 2015, for studies of treatment-naive patients of any age who received FOLFIRINOX as first-line treatment of locally advanced pancreatic cancer. Our primary outcome was overall survival. Secondary outcomes were progression-free survival; rates of grade 3 or 4 adverse events; and the proportion of patients who underwent radiotherapy or chemoradiotherapy, surgical resection after FOLFIRINOX, and R0 resection. We evaluated survival outcomes with the Kaplan-Meier method with patient-level data. Grade 3 or 4 adverse events, and the proportion of patients who underwent subsequent radiotherapy or chemoradiotherapy or resection, were pooled in a random-effects model. FINDINGS: We included 13 studies comprising 689 patients, of whom 355 (52%) patients had locally advanced pancreatic cancer. 11 studies, comprising 315 patients with locally advanced disease, reported survival outcomes and were eligible for patient-level meta-analysis. Median overall survival from the start of FOLFIRINOX ranged from 10·0 months (95% CI 4·0-16·0) to 32·7 months (23·1-42·3) across studies with a pooled patient-level median overall survival of 24·2 months (95% CI 21·7-26·8). Median progression-free survival ranged from 3·0 months (95% CI not calculable) to 20·4 months (6·5-34·3) across studies with a patient-level median progression-free survival of 15·0 months (95% 13·8-16·2). In ten studies comprising 490 patients, 296 grade 3 or 4 adverse events were reported (60·4 events per 100 patients). No deaths were attributed to FOLFIRINOX toxicity. The proportion of patients who underwent radiotherapy or chemoradiotherapy ranged from 31% to 100% across studies. In eight studies, 154 (57%) of 271 patients received radiotherapy or chemoradiotherapy after FOLFIRINOX. The pooled proportion of patients who received any radiotherapy treatment was 63·5% (95% CI 43·3-81·6, I(2) 90%). The proportion of patients who underwent surgical resection for locally advanced pancreatic cancer ranged from 0% to 43%. The proportion of patients who had R0 resection of those who underwent resection ranged from 50% to 100% across studies. In 12 studies, 91 (28%) of 325 patients underwent resection after FOLFIRINOX. The pooled proportion of patients who had resection was 25·9% (95% CI 20·2-31·9, I(2) 24%). R0 resection was reported in 60 (74%) of 81 patients. The pooled proportion of patients who had R0 resection was 78·4% (95% CI 60·2-92·2, I(2) 64%). INTERPRETATION: Patients with locally advanced pancreatic cancer treated with FOLFIRINOX had a median overall survival of 24·2 months-longer than that reported with gemcitabine (6-13 months). Future research should assess these promising results in a randomised controlled trial, and should establish which patients might benefit from radiotherapy or chemoradiotherapy or resection after FOLFIRINOX. FUNDING: None.

Characterising timing and pattern of relapse following surgery for localised oesophagogastric adenocarcinoma: a retrospective study.

BACKGROUND: Oesophagogastric adenocarcinoma (OGA) has a poor prognosis, even for patients with operable disease. However, the optimal surveillance strategy following surgery is unknown. METHODS: We performed a retrospective review of all patients with OGA who had undergone surgery with radical intent at the Royal Marsden between January 2001 and December 2010. RESULTS: Of the 360 patients with OGA who underwent potentially curative surgery, 100/214 patients (47%) with oesophageal/gastro-oesophageal junction (GOJ) adenocarcinoma and 47/146 patients (32%) with gastric adenocarcinoma developed recurrent disease. 51, 79 and 92% of relapses occurred within 1, 2 and 3 years respectively and the majority of patients relapsed at distant sites. Of the patients who relapsed, 67% (67/100) with oesophageal/GOJ adenocarcinoma and 72% of patients with gastric cancer (34/47) were symptomatic at the time of relapse. The majority of asymptomatic relapses were first detected by a rise in tumour markers. There was no difference in disease-free survival between asymptomatic and symptomatic patients, but asymptomatic patients were more likely to receive further treatment and had a longer survival beyond relapse. CONCLUSION: The majority of relapses occur within the first 3 years and at distant sites. Monitoring of tumour markers should be considered as part of a surveillance program.

Does cancer research focus on areas of importance to patients?

The majority of research ideas are proposed by clinicians or scientists and little is currently known about which areas of research patients feel are important. We performed a 4 week pilot patient survey at the Royal Marsden (a specialist cancer centre) to investigate patients' views on priorities for cancer research. A total of 780 patients completed the survey and the top research priorities were identified as: detection and prevention of cancer, scientific understanding, curative treatment and personalised treatment. The top research priorities were remarkably consistent across age, gender and a variety of tumour types. We believe that patients' views should be considered alongside those of clinicians and researchers when devising research proposals and strategies.

Patients' willingness to participate in clinical trials and their views on aspects of cancer research: results of a prospective patient survey.

BACKGROUND: Recruitment to clinical trials can be challenging and slower than anticipated. This prospective patient survey aimed to investigate the proportion of patients approached about a trial who agree to participate, their motivations for trial participation and their views on aspects of cancer research. METHODS: Patients who had been approached about participation in any clinical trials in the Gastrointestinal and Lymphoma Unit at the Royal Marsden were invited to complete a questionnaire. The statistical analysis is mainly descriptive, with percentages being reported. Univariate logistic regression analysis was used to determine any associations between patient characteristics and patient responses. RESULTS: From August 2013-July 2014, 276 patients received 298 clinical trial patient information sheets and were asked to complete the questionnaire. The majority of patients (263 patients, 88 %) consented to a clinical trial and 249 of the 263 patients (95 %) completed the questionnaire. Multiple factors influenced decisions to participate in clinical trials, with patients stating that the most important reasons were that the trial offered the best treatment available and that the trial results could benefit others. Of the 249 questionnaire respondents, 78 % would donate their tissue for genetic research, 75 % would consider participating in studies requiring a research biopsy and 75 % felt that patients should be informed of trial results. Patients treated with palliative intent and those who had received multiple lines of treatment were more willing to consider research biopsies. Of the patients approached about a clinical trial of an investigational medicinal product, 48-50 % would have liked more information on the study drugs/procedures. CONCLUSION: The majority of patients approached about a clinical trial consented to one or more trials. Patients' motivations for trial participation included potential personal benefit and altruistic reasons. A high proportion of patients were willing to donate tissue for research and to consider trials involving repeat biopsies. The majority of patients feel that participants should be informed of trial results and there is a group of patients who would like more detailed trial information.

Management of resectable colorectal lung metastases.

Lung metastases occur in 10-20 % of patients with colorectal cancer. The biology of colorectal lung metastases is poorly understood, however lung metastases are more common in patients with rectal cancer and in patients with RAS mutations. Although the majority of patients have extrapulmonary disease, a small proportion of patients with lung metastases are suitable for lung metastasectomy and surgical resection has become a standard of care, based on data from retrospective series demonstrating a 5-year overall survival of 40-68 %. However, there remains uncertainty regarding the optimal management approach for these patients due to the lack of evidence from randomized controlled trials and current practice varies between institutions. For example, the role for neoadjuvant and adjuvant chemotherapy is not yet defined and there are no randomized trials comparing surgery with alternative treatment options such as radiofrequency ablation and stereotactic ablative radiotherapy. Further research is needed to improve the selection of patients for surgery, but favourable prognostic factors include a normal pre-operative CEA, solitary metastasis, complete resection and a long disease-free interval. There is also evidence that patients with resectable liver and lung metastases may benefit from resection of both sites of disease, and that re-resection may be of benefit in selected patients who relapse with resectable lung metastases. This article summarizes the biology of colorectal lung metastases and discusses the management of patients with lung metastases.

Understanding next generation sequencing in oncology: A guide for oncologists.

DNA sequencing is now faster and cheaper than ever before, due to the development of next generation sequencing (NGS) technologies. NGS is now widely used in the research setting and is becoming increasingly utilised in clinical practice. However, due to evolving clinical commitments, increased workload and lack of training opportunities, many oncologists may be unfamiliar with the terminology and technology involved. This can lead to oncologists feeling daunted by issues such as how to interpret the vast amounts of data generated by NGS and the differences between sequencing platforms. This review article explains common concepts and terminology, summarises the process of DNA sequencing (including data analysis) and discusses the main factors to consider when deciding on a sequencing method. This article aims to improve oncologists' understanding of the most commonly used sequencing platforms and the ongoing challenges faced in expanding the use of NGS into routine clinical practice.

Adjuvant or neoadjuvant therapy for operable esophagogastric cancer?

Esophagogastric cancer encompasses proximal squamous cell carcinoma of the esophagus, distal esophageal/junctional adenocarcinoma of the esophagus and gastric adenocarcinoma. These diseases have different etiologies, geographic incidences and biologies. This review mainly focuses on the treatment of operable esophagogastric adenocarcinoma. In Asia, adjuvant chemotherapy is commonly used for patients with gastric cancer following the landmark ACTS-GC trial. In contrast, perioperative chemotherapy is a standard of care in many Western countries based on the results of the MAGIC trial. Neoadjuvant chemotherapy is better tolerated than adjuvant therapy, and therefore dose intensity is likely to be maintained in a greater proportion of patients. In addition, neoadjuvant treatment can lead to tumor downstaging, increasing the likelihood of achieving a complete surgical resection. This may be particularly important in Western populations, as these patients often present with more advanced tumors than Asian patients. Adjuvant chemoradiotherapy is a standard treatment option in the USA for adenocarcinoma of the stomach or gastroesophageal junction as a result of the INT-0116 trial, but the benefit of this approach after a D2 resection has not been confirmed. Neoadjuvant chemoradiotherapy may reduce the risk of local recurrence and may be particularly beneficial for patients with squamous cell carcinoma as these tumors are more radiosensitive. However, patients with esophagogastric adenocarcinoma are more likely to relapse with distant disease, and therefore a systemic disease approach with chemotherapy is likely to be more beneficial than a purely localized treatment strategy for these patients.

FOLFIRINOX for locally advanced or metastatic pancreatic ductal adenocarcinoma: the Royal Marsden experience.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) has a very poor prognosis. Treatment with FOLFIRINOX has been shown to improve outcomes, but can be associated with significant toxicity. MATERIALS AND METHODS: A retrospective review was performed of all patients with locally advanced or metastatic PDA treated with FOLFIRINOX at the Royal Marsden between November 2010 and November 2013. Efficacy, tolerability, and potential prognostic factors were evaluated. RESULTS: Twenty-seven patients with metastatic PDA and 22 patients with locally advanced PDA were treated with FOLFIRINOX. Patients received a median of 9 cycles (range, 1-26) of FOLFIRINOX. The overall response rate was 41% (20 patients), and a further 17 patients (35%) had stable disease. Thirty-five patients (71%) received FOLFIRINOX in the first-line setting, with a median progression-free survival and overall survival, respectively, of 12.9 months and 18.4 months for patients with locally advanced disease; and 8.4 months and 12.2 months for patients with metastatic disease. The most frequently occurring Grade 3/4 toxicities were neutropenia (29%), fatigue (18%), febrile neutropenia (14%), thromboembolism (12%), and thrombocytopenia (10%). In a univariate analysis, reduction in CA 19-9 of >50% (P < .001), normalization of CA19-9 (P < .001), surgery after FOLFIRINOX (P = .004), and use of prophylactic pegfilgrastim (P = .005) were prognostic for overall survival. CONCLUSION: The efficacy and tolerability of FOLFIRINOX for PDA at our institution is similar to that reported in clinical trials. Careful selection of patients and monitoring of response (according to CA19-9) and toxicities can help maximize advantage in this patient population.

Potential role of rilotumumab in the treatment of gastric cancer.

In 2014, outcomes for patients with advanced gastric cancer remain extremely poor with a high level of unmet need regarding effective therapeutic options. However, recent years have seen increasing interest in the role of the MET signaling pathway in this disease subtype, leading to the development and evaluation of MET-targeted therapeutics. Rilotumumab is a monoclonal antibody directed against hepatocyte growth factor, the only known ligand for the MET receptor. It is an unlicensed product which is currently undergoing evaluation in a randomized Phase III trial in 'MET-positive' gastric cancer. Here we discuss the background to the treatment of gastric cancer as well as the characteristics of rilotumumab and reported results with this agent in the trials performed to date.

Investigational therapies targeting the ErbB family in oesophagogastric cancer.

INTRODUCTION: The prognosis for patients with oesophagogastric (OG) cancer remains poor, with a median survival of approximately 9 - 11 months for patients with metastatic disease. However, a more personalised approach to treatment, using drugs tailored to the molecular characteristics of patients' tumours, has the potential to improve patient outcomes. Drugs targeting the ErbB family of receptors have been developed, but these have had varying degrees of success in clinical practice. AREAS COVERED: The authors provide an overview of the ErbB receptor family with regard to OG cancers. Furthermore, they evaluate the evidence from preclinical and clinical trials of therapeutics targeting this family, including monoclonal antibodies, tyrosine kinase inhibitors and novel agents. EXPERT OPINION: Drugs targeting the ErbB family have been evaluated in OG cancer, with a notable success story in the case of trastuzumab, although there have been disappointing failures with anti-EGFR therapy. The response to targeted treatment remains variable and further biomarker research is essential to identify patients most likely to benefit from these therapies. The treatment of OG cancer remains challenging, but new anti-HER2 therapies and combination therapies hold promise for the future.

The role of personalized medicine in metastatic colorectal cancer: an evolving landscape.

Advances in the treatment of metastatic colorectal cancer have led to an improvement in survival from 12 months with fluorouracil monotherapy to approximately 2 years. This is partly as a result of the addition of irinotecan and oxaliplatin, but is also due to the use of monoclonal antibodies against the epidermal growth factor receptor (EGFR) and antiangiogenic drugs such as bevacizumab. However, there are significant molecular differences between tumours which can affect both prognosis and response to treatment. Personalized medicine aims to tailor treatment according to the characteristics of the individual patient and is now a clinical reality as testing for KRAS mutations to guide treatment with the anti-EGFR monoclonal antibodies cetuximab and panitumumab is now part of routine clinical practice. However, not all patients who are KRAS wild type respond to anti-EGFR therapy and a validated biomarker for antiangiogenic therapy is still lacking. Therefore, other biomarkers are needed to assist with predicting response to both existing drugs as well as to drugs currently under investigation. This review summarizes the molecular biology of colorectal cancer, focusing on the genetic features that are currently most clinically relevant. Current and emerging biomarkers are reviewed along with their roles in selecting patients for targeted treatment with currently licensed therapies and drugs being evaluated in clinical trials. The value of predictive biomarkers of chemosensitivity and potential future treatment strategies are also discussed.