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Mark G Kris

Publications and source records attributed to Mark G Kris.

At least 19 recordsLinked to original sources
PubMed2026

The Genomic Landscape of MYC-, MYCL-, and MYCN-Amplified Solid Tumors.

PURPOSE: MYC, MYCN, and MYCL amplifications are recurrent oncogenic events across solid tumors. Currently, no standardized selection biomarker is available to identify patients with MYC-dependent tumors. EXPERIMENTAL DESIGN: We analyzed copy-number alterations of MYC family genes and their features in more than 68,000 tumor-normal paired samples from pediatric and adult patients sequenced with MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) and annotated with FACETS (Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing). The relationship between amplification features and MYC mRNA expression levels were evaluated in more than 10,000 samples from The Cancer Genome Atlas (TCGA). RESULTS: Across MSK Cancer Center samples, MYC amplifications were most common, found in 2,949 samples compared with 310 in MYCL and 217 in MYCN. Although MYCN and MYCL amplifications were predominantly focal (<10 Mb, 79% and 93%, respectively), MYC amplifications were frequently broader (>10 Mb, 62%). Although most tumor types showed similar features between broad and focal amplifications of MYC, in select cancer types, we identified differing co-occurrence and mutual exclusivity patterns with other disease-specific drivers. Furthermore, although MYC-amplified TCGA samples showed higher mRNA expression than wild-type ones, the focality of MYC amplification was seen to have limited influence on expression levels. CONCLUSIONS: Our results suggest that MYC dependency likely depends on many factors, including, but not limited to, total copy number of the detected amplification, lineage-specific factors, concomitant presence or absence of additional oncogenic alterations, and in some cases amplification focality.

Humans↗
PubMed2021

Immune biomarkers and response to checkpoint inhibition of BRAFV600 and BRAF non-V600 altered lung cancers.

BACKGROUND: While 2-4% of lung cancers possess alterations in BRAF, little is known about the immune responsiveness of these tumours. METHODS: Clinical and genomic data were collected from 5945 patients with lung cancers whose tumours underwent next-generation sequencing between 2015 and 2018. Patients were&#xa0;followed through 2020. RESULTS: In total, 127 patients with metastatic BRAF-altered lung cancers were identified: 29 tumours had Class I mutations, 59 had Class II/III alterations, and 39 had variants of unknown significance (VUS). Tumour mutation burden was higher in Class II/III than Class I-altered tumours (8.8 mutations/Mb versus 4.9, P&#x2009;<&#x2009;0.001), but this difference was diminished when stratified by smoking status. The overall response rate to immune checkpoint inhibitors (ICI) was 9% in Class I-altered tumours and 26% in Class II/III (P&#x2009;=&#x2009;0.25), with median time on treatment of 1.9 months in both groups. Among patients with Class I-III-altered tumours, 36-month HR for death in those who ever versus never received ICI was 1.82 (1.17-6.11). Nine patients were on ICI for >2 years (two with Class I mutations, two with Class II/III alterations, and five with VUS). CONCLUSIONS: A subset of patients with BRAF-altered lung cancers achieved durable disease control on ICI. However, collectively no significant clinical benefit was seen.

Biomarkers, Tumor↗
PubMed2006

Clinical cancer advances 2006: major research advances in cancer treatment, prevention, and screening--a report from the American Society of Clinical Oncology.

A MESSAGE FROM ASCO's PRESIDENT For the second consecutive year, the American Society of Clinical Oncology (ASCO) is publishing Clinical Cancer Advances: Major Research Advances in Cancer Treatment, Prevention, and Screening, an annual review of the most significant cancer research presented or published over the past year. ASCO developed this report to demonstrate the enormous progress being made on the front lines of cancer research today. The report is intended to give all those with an interest in cancer care-the general public, cancer patients and physicians, policymakers, oncologists, and other medical professionals-an accessible summary of the year's most important cancer research advances. These pages report on new targeted therapies that are improving survival and response rates in hard-to-treat cancers such as kidney cancer, HER-2-positive breast cancer, head and neck cancer, and chronic myelogenous leukemia; the FDA's approval of the world's first preventive vaccine for human papillomavirus (HPV), which has the potential to dramatically reduce the global burden of cervical cancer; and advances in the fast-growing field of personalized medicine, including a new lung cancer test that could help physicians better target treatments and predict prognosis. These advances are only part of the landscape. Survival rates are on the rise, the number of cancer deaths in the United States began declining for the first time since 1930, and new research is showing that the rates of certain common cancers, such as those of the breast and colon, have stabilized, and may have even begun to decline. However, cancer research still faces a number of major obstacles. At a time of extraordinary scientific potential, declining federal funding of cancer research threatens to stall or even reverse recent progress. Such funding cuts have already led to fewer clinical trials, fewer talented young physicians entering the field, and a growing bottleneck of basic science discoveries waiting to be "translated" into useful therapies and diagnostics. In addition to highlighting the major research advances over the past year, this report also identifies key barriers to accelerating the pace of cancer research and outlines ASCO's recommendations for overcoming them. Despite these and other challenges, there is much good news on the front lines of cancer research. This report demonstrates the essential role of clinical cancer research in finding new and better ways to treat, diagnose, and prevent a group of diseases that strike half of men and one-third of women in the United States.

Breast Neoplasms↗
PubMed2006

A phase 2 study of TZT-1027, administered weekly to patients with advanced non-small cell lung cancer following treatment with platinum-based chemotherapy.

INTRODUCTION: : TZT-1027, a derivative of dolastatin-10, has a wide spectrum of in vitro activity against cancer cell lines. We conducted a phase 2 trial of TZT-1027 in patients with previously treated non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IV or recurrent NSCLC who had received one prior platinum-based chemotherapy regimen were eligible. Patients received 2.4mg/m(2) of TZT-1027 on days 1 and 8 of a 21-day cycle. The primary endpoint was response rate as measured by RECIST. RESULTS: Thirty-two patients were enrolled (16 women, 16 men). The most common grade 3/4 adverse effects were leukopenia and neutropenia. Four patients died within 30 days of receiving TZT-1027, three from progressive disease and one with pneumonia and neutropenia. No objective response was observed (0% observed rate, 95% confidence interval 0-11%). The median time to progression was 1.5 months. The median overall survival was 8.5 months. CONCLUSIONS: This phase 2 trial showed that TZT-1027 administered on days 1 and 8 of a 21-day cycle had no anticancer activity. Further development of TZT-1027 in patients with previously treated NSCLC is not warranted.

Adult↗
PubMed2006

Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors.

PURPOSE: In patients whose lung adenocarcinomas harbor epidermal growth factor receptor (EGFR) tyrosine kinase domain mutations, acquired resistance to the tyrosine kinase inhibitors (TKI) gefitinib (Iressa) and erlotinib (Tarceva) has been associated with a second-site EGFR mutation, which leads to substitution of methionine for threonine at position 790 (T790M). We aimed to elucidate the frequency and nature of secondary EGFR mutations in patients with acquired resistance to TKI monotherapy. EXPERIMENTAL DESIGN: Tumor cells from patients with acquired resistance were examined for secondary EGFR kinase domain mutations by molecular analyses. RESULTS: Eight of 16 patients (50% observed rate; 95% confidence interval, 25-75%) had tumor cells with second-site EGFR mutations. Seven mutations were T790M and one was a novel D761Y mutation found in a brain metastasis. When combined with a drug-sensitive L858R mutation, the D761Y mutation modestly reduced the sensitivity of mutant EGFR to TKIs in both surrogate kinase and cell viability assays. In an autopsy case, the T790M mutation was found in multiple visceral metastases but not in a brain lesion. CONCLUSIONS: The T790M mutation is common in patients with acquired resistance. The limited spectrum of TKI-resistant mutations in EGFR, which binds to erlotinib in the active conformation, contrasts with a wider range of second-site mutations seen with acquired resistance to imatinib, which binds to ABL and KIT, respectively, in closed conformations. Collectively, our data suggest that the type and nature of kinase inhibitor resistance mutations may be influenced by both anatomic site and mode of binding to the kinase target.

Adenocarcinoma↗
PubMed2006

Pharmacokinetics and toxicity of weekly docetaxel in older patients.

PURPOSE: To evaluate the pharmacokinetics of weekly docetaxel in a cohort of older patients with metastatic cancer and to explore the relationship of pharmacokinetic variables, Erythromycin Breath Test results, age, geriatric assessment variables, and toxicity to therapy. EXPERIMENTAL DESIGN: Twenty patients ages > or = 65 years with metastatic breast, prostate, or lung cancer entered an Institutional Review Board-approved protocol to evaluate the pharmacokinetics of weekly docetaxel administered at 35 mg/m2 i.v. for 3 weeks followed by a 1-week break. The Erythromycin Breath Test and geriatric assessment were done before the first dose. Blood samples were collected for pharmacokinetic analysis with the first dose of docetaxel. RESULTS: Of the 20 patients who entered the study, 19 were evaluable. There were no age-related differences in the pharmacokinetics of weekly docetaxel. Fifty-eight percent (11 of 19) experienced grade > or = 3 toxicity: 16% (3 of 19) grade > or = 3 hematologic toxicity, and 53% (10 of 19) grade > or = 3 nonhematologic toxicity. There was an association between the Erythromycin Breath Test results and docetaxel pharmacokinetic variables; however, there was no association between Erythromycin Breath Test results or docetaxel pharmacokinetics with frequency of grade > or = 3 toxicity. CONCLUSIONS: Despite no statistically significant age-related differences in weekly docetaxel pharmacokinetics, over half of these older patients experienced a grade > or = 3 toxicity at the 35 mg/m2 starting dose. We advocate a starting dose of 26 mg/m2 on this weekly schedule and dose escalating if no toxicity.

Aged↗
PubMed2006

A phase I/II study of weekly high-dose erlotinib in previously treated patients with nonsmall cell lung cancer.

BACKGROUND: Preclinical studies have suggested that erlotinib at high doses may inhibit additional sites downstream of the epidermal growth factor receptor (EGFR), resulting in greater antitumor efficacy. The objective of this study was to determine the tolerability and efficacy of high-dose erlotinib administered on a weekly schedule to patients with advanced nonsmall cell lung cancer (NSCLC). METHODS: The authors conducted a Phase I/II trial of weekly erlotinib in patients with progressive NSCLC who had received previous chemotherapy. In the Phase I portion, patients were enrolled in 3-patient cohorts at erlotinib dose levels of 1200 mg, 1600 mg, and 2000 mg once weekly. The Phase II portion was designed to determine the major objective response rate of the dose identified in the Phase I portion of the trial. RESULTS: Twenty-seven patients were enrolled. No dose-limiting toxicity was observed. Grade 1 and 2 rash and diarrhea were the principle toxicities, and each occurred in 92% of patients. Among 21 patients who were treated at the Phase II dose of 2000 mg weekly, a single objective response was identified, yielding a response rate of 5% (95% confidence interval, 0.2-22%). For this cohort, the median survival was 9.5 months. The sole radiographic response occurred in a patient whose pretreatment tumor specimen harbored an EGFR exon 19 deletion. CONCLUSIONS: Erlotinib at a dose of 2000 mg administered weekly was tolerated well by these patients with advanced NSCLC. The 5% objective response rate did not reach the stated objective at the interim efficacy analysis, prompting the closure of the study.

Adult↗
PubMed2006

A phase I trial of intermittent high-dose gefitinib and fixed-dose docetaxel in patients with advanced solid tumors.

PURPOSE: Based on our mouse xenograft model demonstrating that intermittent high-dose gefitinib sensitizes tumors to subsequent treatment with taxanes, we initiated this phase I trial to explore docetaxel in combination with escalating doses of intermittent gefitinib (Iressa) given prior to docetaxel. METHODS: This was a phase I study where patients with advanced cancer were treated with escalating doses of gefitinib (1,000, 1,500, 2,250, 3,000 mg) on days 1 and 2 followed by docetaxel (75 mg/m2) on day 3 of a 21 day cycle. Gefitinib pharmacokinetic data were obtained on days 1, 2, and 3 of cycles 1 and 2 at each dose level. RESULTS: 18 patients were enrolled in this study with the most frequent tumor types being non-small cell lung cancer and head and neck squamous cell cancer. The dose-limiting toxicity was neutropenia (n=1 at dose level 2, n=2 at dose level 4). Rash, diarrhea, and fatigue were the most common grade 1-2 toxicities. Pharmacokinetic data indicated no accumulation of gefitinib between cycles 1 and 2 and no clear correlation between gefitinib plasma levels and toxicity. Partial responses were observed in one patient with head and neck squamous cell carcinoma and one patient with anaplastic thyroid cancer. CONCLUSION: The recommended dose for phase II studies is gefitinib 2,250 mg on days 1 and 2, followed by docetaxel 75 mg/m2 on day 3.

Adult↗
PubMed2006

American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006.

PURPOSE: To update the 1999 American Society of Clinical Oncology guideline for antiemetics in oncology. UPDATE METHODOLOGY: The Update Committee completed a review and analysis of data published from 1998 thru February 2006. The literature review focused on published randomized controlled trials, and systematic reviews and meta-analyses of published phase II and phase III randomized controlled trials. RECOMMENDATIONS: The three-drug combination of a 5-hydroxytryptamine-3 (5-HT(3)) serotonin receptor antagonist, dexamethasone, and aprepitant is recommended before chemotherapy of high emetic risk. For persons receiving chemotherapy of high emetic risk, there is no group of patients for whom agents of lower therapeutic index are appropriate first-choice antiemetics. These agents should be reserved for patients intolerant of or refractory to 5-HT3 serotonin receptor antagonists, neurokinin-1 receptor antagonists, and dexamethasone. The three-drug combination of a 5-HT3 receptor serotonin antagonist, dexamethasone, and aprepitant is recommended for patients receiving an anthracycline and cyclophosphamide. For patients receiving other chemotherapy of moderate emetic risk, the Update Committee continues to recommend the two-drug combination of a 5-HT3 receptor serotonin antagonist and dexamethasone. In all patients receiving cisplatin and all other agents of high emetic risk, the two-drug combination of dexamethasone and aprepitant is recommended for the prevention of delayed emesis. The Update Committee no longer recommends the combination of a 5-HT3 serotonin receptor antagonist and dexamethasone for the prevention of delayed emesis after chemotherapeutic agents of high emetic risk. CONCLUSION The Update Committee recommends that clinicians administer antiemetics while considering patients' emetic risk categories and other characteristics.

Antiemetics↗
PubMed2006

Use of cigarette-smoking history to estimate the likelihood of mutations in epidermal growth factor receptor gene exons 19 and 21 in lung adenocarcinomas.

PURPOSE: Lung adenocarcinomas with mutations in exons 19 and 21 of the epidermal growth factor receptor gene (EGFR) demonstrate sensitivity to gefitinib or erlotinib. Investigators have reported an association between EGFR mutations and the amount and duration of cigarette smoking, with the highest incidence of mutations seen in never smokers. METHODS: EGFR exon 19 and 21 mutation status was determined in 265 tumor samples using direct sequencing, polymerase chain reaction (PCR), or PCR-based restriction fragment length polymorphism analysis. A detailed smoking history was obtained. Patients were categorized as never smokers (< 100 lifetime cigarettes), former smokers (quit > or = 1 year ago), or current smokers (quit < 1 year ago). RESULTS: We detected EGFR mutations in 34 (51%) of 67 never smokers (95% CI, 38% to 64%), 29 (19%) of 151 former smokers (95% CI, 13% to 27%), and two (4%) of 47 current smokers (95% CI, 1% to 16%). Significantly fewer EGFR mutations were found in people who smoked for more than 15 pack-years (P < .001) or stopped smoking less than 25 years ago (P < .02) compared with individuals who never smoked. The number of smoking pack-years and smoke-free years predicted the prevalence of EGFR mutations (areas under receiver operating characteristic curve = 0.78 and 0.77, respectively). CONCLUSION: The likelihood of EGFR mutations in exons 19 and 21 decreases as the number of pack-years increases. Mutations were less common in people who smoked for more than 15 pack-years or who stopped smoking cigarettes less than 25 years ago. These data can assist clinicians in assessing the likelihood of exon 19 and 21 EGFR mutations in patients with lung adenocarcinoma when mutational analysis is not feasible.

Adenocarcinoma↗
PubMed2006

Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib.

PURPOSE: In patients with non-small cell lung cancer (NSCLC), mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain have been associated with sensitivity to erlotinib and gefitinib. We undertook this study to explore the relationship between EGFR mutation type and clinical variables, including treatment with gefitinib and erlotinib. EXPERIMENTAL DESIGN: In patients with NSCLC, EGFR exon 19 deletion mutations and EGFR L858R point mutations were analyzed by nonsequencing PCR-based methods from paraffin blocks of tissue obtained before treatment. The results were correlated with clinical information (sex, pathologic subtype, race/ethnicity, treatment, and overall survival). RESULTS: The two most common EGFR mutations were identified in 24% (70 of 291; 95% confidence interval, 26%-38%) of tumors from patients with NSCLC. EGFR mutation was associated with Asian ethnicity (P = 0.0023) and being a "never smoker" (P = 0.0001). Among patients with EGFR mutations, 39% (27 of 70) had EGFR L858R, whereas 61% (43 of 70) had an EGFR exon 19 deletion. After treatment with erlotinib (n = 12) or gefitinib (n = 22), patients with EGFR mutations had a median overall survival of 20 months. After treatment with erlotinib or gefitinib, patients with EGFR exon 19 deletions had significantly longer median survival than patients with EGFR L858R (34 versus 8 months; log-rank P = 0.01). CONCLUSIONS: EGFR mutations in exons 19 or 21 are correlated with clinical factors predictive of response to gefitinib and erlotinib. Those with EGFR exon 19 deletion mutations had a longer median survival than patients with EGFR L858R point mutation. These observations warrant confirmation in a prospective study and exploration of the biological mechanisms of the differences between the two major EGFR mutations.

Adult↗
PubMed2006

Patient versus clinician symptom reporting using the National Cancer Institute Common Terminology Criteria for Adverse Events: results of a questionnaire-based study.

BACKGROUND: The Common Terminology Criteria for Adverse Events (CTCAE) are used as standard practice in trials of cancer treatments by clinicians to elicit and report toxic effects. Alternatively, patients could report this information directly as patient-reported outcomes, but the accuracy of these reports compared with clinician reports remains unclear. We aimed to compare the reporting of symptom severity reported by patients and clinicians. METHODS: Between March and May, 2005, a questionnaire with 11 common CTCAE symptoms was given to consecutive outpatients and their clinicians (physicians and nurses) in lung and genitourinary cancer clinics in the Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Patients completed a version that used language adapted from the CTCAE for patient self-reporting. The results from the questionnaire were compared with clinician reporting of the same symptoms. FINDINGS: Of 435 patients and their clinicians asked to take part in the study, 400 paired surveys were completed. For most symptoms, agreement between patient and clinician was high, and most discrepancies were within a grade difference of one point. Agreement was higher for symptoms that could be observable directly, such as vomiting and diarrhoea, than for more subjective symptoms, such as fatigue and dyspnoea. Differences in symptom reporting rarely would have changed treatment decisions or dosing, and patients assigned greater severity to symptoms more than did clinicians. No significant differences were recorded between the results when the questionnaire was completed by the patient before or after the clinician. INTERPRETATION: Patient reporting of symptoms could add to the current approach to symptom monitoring in cancer treatment trials. Future research should assess the effect of self reporting on clinical outcomes and efficiency, and the use of real-time collection of patient-reported outcomes for early detection of potentially serious adverse events.

Adult↗
PubMed2006

Lung cancer: computerized quantification of tumor response--initial results.

PURPOSE: To prospectively quantify tumor response or progression in patients with lung cancer by using thin-section computed tomography (CT) and a semiautomated algorithm to calculate tumor volume and other parameter values. MATERIALS AND METHODS: This HIPAA-compliant study was institutional review board approved; informed patient consent was waived. CT scans of 15 measurable non-small cell lung cancers (in five men and 10 women; mean age, 64 years; range, 38-78 years) before and after gefitinib treatment were analyzed. A semiautomated three-dimensional lung cancer segmentation algorithm was developed and applied to each tumor at baseline and follow-up. The computer calculated the greatest diameter (unidimensional measurement), the product of the greatest diameter and the greatest perpendicular diameter (bidimensional measurement), and the volume of each tumor. Exact McNemar tests were used to analyze differences in the percentage change calculated with different measurement techniques. RESULTS: The computer accurately segmented 14 of the 15 tumors. One paramediastinal tumor required manual separation from the mediastinum. Eleven (73%) of the 15 patients had an absolute change in tumor volume of at least 20%, compared with one (7%) and four (27%) patients who had similar changes in unscaled unidimensional (P < .01) and bidimensional (P = .04) tumor measurements, respectively. Seven (47%) patients had an absolute change in tumor volume of at least 30%. In contrast, at unscaled analysis, no patients at unidimensional measurement (P = .02) and two (13%) patients at bidimensional measurement (P = .06) had a change of at least 30%. CONCLUSION: Compared with the unidimensional and bidimensional techniques, semiautomated tumor segmentation enabled the identification of a larger number of patients with absolute changes in tumor volume of at least 20% and 30%.

Adult↗
PubMed2005

Clinical Cancer Advances 2005: major research advances in cancer treatment, prevention, and screening--a report from the American Society of Clinical Oncology.

This year, for the first time, the American Society of Clinical Oncology (ASCO) is publishing Clinical Cancer Advances 2005: Major Research Advances in Cancer Treatment, Prevention, and Screening, an annual review of the most significant clinical research presented or published over the past year across all cancer types. ASCO embarked on this project to provide the public, patients, policymakers, and physicians with an accessible summary of the year's most important research advances. While not intended to serve as a comprehensive review, this report provides a year-end snapshot of research that will have the greatest impact on patient care. As you will read, there is much good news from the front lines of cancer research. These pages report on new chemotherapy regimens that sharply reduce the risk of recurrence for very common cancers; the "coming of age" of targeted cancer therapies; promising studies of drugs to prevent cancer; and improvements in quality of life for people living with the disease, among many other advances. Survival rates for cancer are on the rise, increasing from 50% to 64% over the last 30 years. Cancer still exacts an enormous toll, however. Nearly 1.4 million Americans will be diagnosed this year, and some 570,000 will die of the disease. Clearly, more research is needed to find effective therapies for the most stubborn cancer types and stages. We need to know more about the long-term effects of newer, more targeted cancer therapies, some of which need to be taken over long periods of time. And we need to devote far greater attention to tracking and improving the care of the nearly 10 million cancer survivors in the United States today. Despite these and other challenges, the message of this report is one of hope. Through the dedicated, persistent pursuit of clinical research and participation in clinical trials by people with cancer, we steadily uncover new and better ways of treating, diagnosing, and preventing a disease that touches the lives of so many. I want to thank the Editorial Board members, the Specialty Editors, and the ASCO Cancer Communications Committee for their dedicated work to develop this report, and I hope you find it useful.

Breast Neoplasms↗