Maeve A Lowery

Memorial Sloan-Kettering Cancer Center, New York, New York, United States

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Publications (31)82.88 Total impact

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    ABSTRACT: Background: Pancreatic adenocarcinoma (PAC) is part of several cancer predisposition syndromes; however, indications for genetic counseling/testing are not well-defined. In the current study, the authors sought to determine mutation prevalence and characteristics that are predictive of an inherited predisposition for PAC. Methods: A total of 175 consecutive patients with PAC who underwent clinical genetics assessment at Memorial Sloan Kettering Cancer Center between 2011 and 2014 were identified. Clinical data, family history, and germline results were evaluated. Results: Among 159 patients with PAC who pursued genetic testing, 24 pathogenic mutations were identified (15.1%; 95% confidence interval, 9.5%-20.7%), including BRCA2 (13 mutations), BRCA1 (4 mutations), p16 (2 mutations), PALB2 (1 mutation), and Lynch syndrome (4 mutations). BRCA1/BRCA2 prevalence was 13.7% in Ashkenazi Jewish (AJ) patients (95 patients) and 7.1% in non-AJ patients (56 patients). In AJ patients with a strong, weak, or absent family history of BRCA-associated cancers, the mutation prevalence was 16.7%, 15.8%, and 7.4%, respectively. The mean age at the time of diagnosis in all mutation carriers was 58.5 years (range, 45-75 years) compared with 64 years (range, 27-87 years) in those not carrying a mutation (P = .02). Although BRCA2 was the most common mutation identified, no patients with early-onset PAC (diagnosed at age ≤ 50 years) harbored a BRCA2 mutation and the mean age at diagnosis in BRCA2 carriers was equivalent to that of individuals who were not mutation carriers (P = .34). Mutation prevalence in patients with early-onset disease (21 patients) was 28.6%, including BRCA1 (2 mutations), p16 (2 mutations), MSH2 (1 mutation), and MLH1 (1 mutation). Conclusions: Mutations in BRCA2 account for > 50% of patients with PAC with an identified susceptibility syndrome. AJ patients were found to have high BRCA1/BRCA2 prevalence regardless of personal/family history, suggesting that ancestry alone indicates a need for genetic evaluation. With the exception of BRCA2-associated PAC, an inherited predisposition for PAC is associated with an earlier age at PAC diagnosis, suggesting that this subset of patients may also represent a population warranting further evaluation. Cancer 2015. © 2015 American Cancer Society.
    No preview · Article · Oct 2015 · Cancer
  • Maeve A Lowery · Eileen M O'Reilly
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    ABSTRACT: The last decade has seen significant developments in the use of combination systemic therapy for advanced pancreatic ductal adenocarcinoma (PDAC), with median survival approaching 1 year for select patients treated with FOLFIRINOX in the metastatic setting. However, it is sobering that these developments have been achieved with the use of traditional cytotoxics rather than from successes in the more modern fields of molecularly targeted therapies or immunotherapy. This article highlights several promising therapeutic approaches to PDAC currently under clinical evaluation, including immune therapies, molecularly targeted therapies, strategies for stromal depletion, and targeted therapy for genetically selected patients. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Aug 2015 · Hematology/oncology clinics of North America
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    ABSTRACT: For patients with metastatic pancreatic adenocarcinoma, there are no approved or established treatments beyond the 2nd line. A Phase Ib study of fractionated radioimmunotherapy was undertaken in this setting, administering (90)Y-clivatuzumab tetraxetan (yttrium-90-radiolabelled humanised antibody targeting pancreatic adenocarcinoma mucin) with or without low radiosensitising doses of gemcitabine. Fifty-eight patients with three (2-7) median prior treatments were treated on Arm A (N=29, (90)Y-clivatuzumab tetraxetan, weekly 6.5mCi/m(2)doses×3, plus gemcitabine, weekly 200mg/m(2) doses×4 starting 1week earlier) or Arm B (N=29, (90)Y-clivatuzumab tetraxetan alone, weekly 6.5mCi/m(2)doses×3), repeating cycles after 4-week delays. Safety was the primary endpoint; efficacy was also evaluated. Cytopaenias (predominantly transient thrombocytopenia) were the only significant toxicities. Fifty-three patients (27 Arm A, 26 Arm B, 91% overall) completed ⩾1 full treatment cycles, with 23 (12 Arm A, 11 Arm B; 40%) receiving multiple cycles, including seven (6 Arm A, 1 Arm B; 12%) given 3-9 cycles. Two patients in Arm A had partial responses by RECIST criteria. Kaplan-Meier overall survival (OS) appeared improved in Arm A versus B (hazard ratio [HR] 0.55, 95% CI: 0.29-0.86; P=0.017, log-rank) and the median OS for Arm A versus Arm B increased to 7.9 versus 3.4months with multiple cycles (HR 0.32, P=0.004), including three patients in Arm A surviving >1year. Clinical studies of (90)Y-clivatuzumab tetraxetan combined with low-dose gemcitabine appear feasible in metastatic pancreatic cancer patients beyond 2nd line and a Phase III trial of this combination is now underway in this setting. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
    No preview · Article · Jul 2015 · European journal of cancer (Oxford, England: 1990)

  • No preview · Article · Jul 2015 · Cancer Research
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    ABSTRACT: Reports show that FOLFIRINOX therapy for pancreatic ductal adenocarcinoma (PDAC) results in objective response rates two to threefold higher than those of other regimens. This study aimed to assess response and resection rates for locally unresectable (stage 3) patients initially treated with induction FOLFIRINOX. The institutional cancer database was queried for patients treated with induction FOLFIRINOX therapy between 2010 and 2013. Patients were included in the study if they were treated at the authors' institution for stage 3 PDAC (locally unresectable) that had been adjudicated at a weekly multidisciplinary tumor board. The study identified 101 patients. The median age was 64 years (range 37-81 years), and the median follow-up period was 12 months (range 3-37 months). The patients received a median of six cycles (range 1-20 cycles) of induction FOLFIRINOX. No grade 4 or 5 toxicity was recorded. At the initial restaging (median of 3 months after diagnosis), 23 patients (23 %) had developed distant metastases, 15 patients (15 %) had undergone resection, and 63 patients (63 %) had proceeded to chemoradiation. In the group of 63 patients who had proceeded to chemoradiation (median of 9 months after diagnosis), an additional 16 patients (16 %) had undergone resection, and 5 patients (5 %) had developed metastases. A partial radiographic response was observed in 29 % of all the patients, which was associated with ability to perform resection (p = 0.004). The median overall survival time was 11 months for the group that progressed with FOLFIRINOX and 26 months for the group that did not progress. Nearly one third of the patients who had been initially identified as having stage 3 pancreatic carcinoma and had been treated with FOLFIRINOX responded radiographically and underwent tumor resection.
    No preview · Article · Jun 2015 · Annals of Surgical Oncology
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    ABSTRACT: Pancreas adenocarcinoma has a median age at diagnosis of 71 years. Limited studies have focused on the treatment of elderly patients with pancreas cancer. An analysis of systemic therapy use, clinical trial participation, and overall outcomes of 237 patients with metastatic pancreas adenocarcinoma ≥ 75 years of age evaluated at Memorial Sloan-Kettering Cancer Center between 2005 and 2013 was undertaken. Median overall survival was 7 months for the entire study population. A total of 197 (83%) patients received systemic therapy, which was significantly associated with longer overall survival (P < .01). No significant difference was detected in survival between age groups 75 to 79, 80 to 84, and ≥ 85 years of age among those who received systemic therapy (P = .49). Seventy-seven (32%) patients participated in a clinical trial of whom 13 (5%) patients were enrolled in a therapeutic trial, including no patients aged ≥ 85 years. Multivariate analysis demonstrated that presence of liver metastases (P < .001), performance status (P < .001), and number of systemic agents (P < .001) were significantly associated with survival. Receipt of systemic therapy was associated with longer survival in elderly patients ≥ 75 years of age with metastatic pancreas adenocarcinoma. Therapeutic clinical trial participation among these patients was low and future development of prognostic models for appropriate patient selection is warranted. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · May 2015 · Clinical Colorectal Cancer
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    ABSTRACT: Objectives: Acinar cell carcinoma (ACC), including its mixed variants, is a rare pancreatic malignancy. Recent reports have documented its occurrence in Lynch syndrome. Our aim was to evaluate the frequency and clinicopathologic significance of DNA mismatch repair (MMR) deficiency in ACCs in general. Methods: Mismatch repair protein expression was evaluated by immunohistochemistry in a series of 36 ACC cases that were treated at our institution and had sufficient clinical information and pathologic material. Results: Loss of MMR protein was observed in 5 ACCs (5/36, 14%): 2 lost MLH1/PMS2, 2 lost MSH2/MSH6, and 1 lost MSH6 alone. The 1 MSH6-deficient case and 1 of the 2 MSH2/MSH6-deficient cases had a known history of Lynch syndrome, carrying a germline mutation in MSH6 and MSH2, respectively. None of the 5 tumors showed distinctive morphology. Two of the 5 patients died of disease 6 and 21 months after diagnosis. In contrast, in the MMR-normal group, only 1 of 30 patients died of disease (median follow-up, 32.5 months). Conclusions: Mismatch repair protein deficiency is not uncommon in ACCs, occurring in 14% of the cases in this series. The MMR-deficient ACCs did not show distinctive morphologic features and were clinically no less aggressive than MMR-normal ACCs.
    No preview · Article · Nov 2014 · Pancreas
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    ABSTRACT: Background Nucleotide transporters such as human equilibrative nucleoside transporter-1 (hENT1) play a major role in transporting gemcitabine into cells. CO-1.01 (gemcitabine-5′-elaidate) is a novel cytotoxic agent consisting of a fatty acid derivative of gemcitabine, which is transported intracellularly independent of hENT1. CO-1.01 was postulated to have efficacy as a second-line treatment in gemcitabine-refractory pancreatic adenocarcinoma in patients with negative tumor hENT1 expression. Methods Eligibility criteria included patients with either a newly procured or archival biopsy tumor confirming the absence of hENT1 and either gemcitabine-refractory metastatic pancreas adenocarcinoma or with progression of disease following resection during or within 3 months of adjuvant gemcitabine therapy. Patients were treated with intravenous infusion of CO-1.01 dosed at 1250 mg/m2 on Days 1, 8, and 15 of a 4-week cycle. The primary end point was disease control rate (DCR). Results Nineteen patients were enrolled of which 18 patients were evaluable for efficacy assessment. Thirteen patients (68%) had liver metastases, 6 (32%) had lymph node metastases, and 10 (53%) had lung metastases. Two of 18 patients (11%) achieved disease control. The median survival time was 4.3 (95% CI 2.1–8.1) months. All patients experienced at least one treatment-related adverse event with the majority of events being mild or moderate. Conclusion This study did not meet its primary endpoint and no efficacy signal was identified for CO-1.01 in treating progressive metastatic pancreas adenocarcinoma.
    No preview · Article · Sep 2014 · Pancreatology
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    ABSTRACT: Purpose: Despite a challenging prognosis, modern cytotoxic therapy can induce tumor responses and extend life in pancreatic adenocarcinoma (PDAC). Pharmacogenomic (PGx) modeling of tumor tissue can predict the efficacy of chemotherapeutic agents in preclinical cancer models. We hypothesized that PGx profiling of circulating tumor and invasive cells (CTIC) isolated from peripheral blood could predict tumor response, progression, and resistance. Experimental design: A PGx model was created and validated in preclinical models. A prospective clinical trial was conducted. Fifty patients with advanced PDAC were enrolled. Before treatment, 10 mL of peripherally drawn blood was collected. CTICs isolated from this blood sample were expression profiled and the PGx model was used to predict effective and ineffective chemotherapeutic agents. The treating physicians were blinded to PGx prediction. Results: We found that CTICs could be reliably isolated, total RNA extracted and profiled from 10 mL of peripheral blood from patients with unresectable PDAC before chemotherapy treatment and at disease progression. Using previously created PGx models to predict chemotherapy sensitivity, we found that clinical benefit was seen for study participants treated with chemotherapy regimens predicted to be effective versus chemotherapy regimens predicted to be ineffective with regard to progression-free (10.4 mo vs. 3.6 mo; P < 0.0001; HR, 0.14) and overall survival (17.2 mo vs. 8.3 mo; P < 0.0249; HR, 0.29). Conclusions: These findings suggest that PGx profiling of CTICs can predict treatment response.
    Preview · Article · Aug 2014 · Clinical Cancer Research
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    ABSTRACT: Objectives: Acinar cell carcinoma (ACC), including its mixed variants, is a rare pancreatic malignancy. Recent reports have documented its occurrence in Lynch syndrome. Our aim was to evaluate the frequency and clinicopathologic significance of DNA mismatch repair (MMR) deficiency in ACCs in general. Methods: Mismatch repair protein expression was evaluated by immunohistochemistry in a series of 36 ACC cases that were treated at our institution and had sufficient clinical information and pathologic material. Results: Loss of MMR protein was observed in 5 ACCs (5/36, 14%): 2 lost MLH1/PMS2, 2 lost MSH2/MSH6, and 1 lost MSH6 alone. The 1 MSH6-deficient case and 1 of the 2 MSH2/MSH6-deficient cases had a known history of Lynch syndrome, carrying a germline mutation in MSH6 and MSH2, respectively. None of the 5 tumors showed distinctive morphology. Two of the 5 patients died of disease 6 and 21 months after diagnosis. In contrast, in the MMR-normal group, only 1 of 30 patients died of disease (median follow-up, 32.5 months). Conclusions: Mismatch repair protein deficiency is not uncommon in ACCs, occurring in 14% of the cases in this series. The MMR-deficient ACCs did not show distinctive morphologic features and were clinically no less aggressive than MMR-normal ACCs.
    No preview · Article · Jul 2014 · Pancreas
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    ABSTRACT: Background: The role for neoadjuvant systemic therapy in resectable pancreas adenocarcinoma remains undefined. Objective: We evaluated the efficacy of gemcitabine and oxaliplatin administered as preoperative therapy in patients with resectable pancreas adenocarcinoma. Methods: Eligible patients were screened using computed tomography-pancreas angiography, laparoscopy, endoscopic ultrasonography, and fine-needle aspiration cytology to identify 38 patients who received 4 cycles of neoadjuvant gemcitabine 1000 mg/m(2) intravenously over 100 minutes and oxaliplatin 80 mg/m(2) intravenously over 2 hours, every 2 weeks. Patients whose tumors remained resectable at restaging proceeded to operation and subsequently received 5 cycles of adjuvant gemcitabine (1000 mg/m(2) intravenously over 30 minutes days 1, 8, and 15 every 4 weeks). The primary endpoint was 18-month overall survival and secondary endpoints included radiological, tumor marker and pathological response to neoadjuvant therapy, time to recurrence, patterns of failure, and feasibility of obtaining preoperative core biopsies. Results: Thirty-five of 38 patients (92%) completed neoadjuvant therapy. Twenty-seven patients underwent tumor resection (resectability rate 71%), of which 26 initiated adjuvant therapy for a total of 23 patients (60.5%) who completed all planned therapy. The 18-month survival was 63% (24 patients alive). The median overall survival for all 38 patients was 27.2 months (95% confidence interval: 17-NA) and the median disease-specific survival was 30.6 months (95% confidence interval: 19-NA). Conclusions: This study met its endpoint and provided a signal suggesting that exploration of neoadjuvant systemic therapy is worthy of further investigation in resectable pancreas adenocarcinoma. Improved patient selection and more active systemic regimens are key.
    No preview · Article · Jul 2014 · Annals of Surgery
  • Maeve A Lowery · Eileen M O'Reilly

    No preview · Article · Mar 2014 · Oncology (Williston Park, N.Y.)

  • No preview · Article · Jan 2013
  • Eileen M O'Reilly · Maeve A Lowery
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    ABSTRACT: Approximately 15% of patients with a diagnosis of pancreatic adenocarcinoma are candidates for potentially curative surgery. However, most patients who undergo such surgery will die from recurrent disease, most within the first few years, whereas nearly all succumb by 5 to 7 years from diagnosis. Currently, there is a lack of high-level evidence to guide consensus recommendations as to the optimal surveillance strategy after resection. There is considerable variability in clinical practice, ranging from frequent clinical follow-up, with serial Ca 19-9 measurement and routine computed tomographic imaging on a 3- to 6-monthly basis, to a practice of no routine serum or imaging follow-up after surgery. In most part, this divergence in practice reflects a lack of data to define optimal practice. The argument in favor of limited surveillance presumably stems from the relatively uniform poor outcomes after recurrence and the absence of evidence indicating that early detection of local, regional, or metastatic recurrence improves outcomes. However, recent advancements in the treatment of metastatic disease offer hope that earlier detection and initiation of treatment for recurrent disease may positively impact clinical outcomes and at least urges review of the topic. One advantage to the development of defined guidelines would be greater consistency in the setting of both routine clinical follow-up and follow-up after adjuvant therapy on trial.
    No preview · Article · Nov 2012 · The Cancer Journal
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    Preview · Article · Jul 2012 · Gastrointestinal cancer research: GCR
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    Full-text · Article · May 2012 · Gastrointestinal cancer research: GCR
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    Preview · Article · Mar 2012 · Gastrointestinal cancer research: GCR
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    Full-text · Article · Mar 2012 · Gastrointestinal cancer research: GCR
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    ABSTRACT: Acinar cell carcinoma (ACC) of the pancreas is a rare neoplasm, accounting for 1% of all pancreatic neoplasms. There remains a lack of data regarding the use of systemic therapy in this disease. We present a series of 40 consecutive cases of ACC of the pancreas treated at Memorial Sloan-Kettering Cancer Center, with an emphasis on evaluation of activity of new therapeutic agents. Patients reviewed at our institution from January 2000 through January 2011 were identified from an institutional database with prior institutional review board approval. Pathology was confirmed in all cases as ACC or a closely related entity. Forty patients were identified; 29 were male (73%). The median age at diagnosis was 65 years (range, 16-87 years). The median overall survival (OS) time for patients with localized, resectable disease was 56.9 months and the OS time for patients with metastatic ACC (n = 18) was 19.6 months. Six patients with metastatic or recurrent ACC had a partial response to chemotherapy and five patients had stable disease for ≥6 months on systemic chemotherapy. Clinical observation was made of a patient with ACC and hereditary nonpolyposis colorectal cancer and a patient with ACC and a BRCA1 germline mutation. ACC is moderately chemoresponsive to agents that have activity in pancreatic adenocarcinoma and colorectal carcinoma. A potential association between germline mutations in DNA mismatch repair genes and ACC warrants further evaluation.
    Preview · Article · Dec 2011 · The Oncologist
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    MA Lowery · E M O'Reilly
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    ABSTRACT: The last decade has brought significant advances in the development of molecularly targeted therapies for treatment of a variety of human malignancies. In contrast to other solid tumors, however, the impact of novel therapeutic strategies on clinical outcomes in patients with pancreas adenocarcinoma (PAC) has been limited to date. Gemcitabine was established as a standard of care for treatment of advanced PAC in 1997 based on an observed improvement in clinical benefit as adjudicated principally by pain scores and analgesic consumption, and demonstration of an overall survival (OS) benefit in a randomized comparison with 5-fluorouracil (5-FU). Since then, multiple agents targeting oncogenic signaling pathways and mediators of angiogenesis have failed to improve outcomes in phase III clinical trials when compared with gemcitabine monotherapy. An exception to this is the anti-epidermal growth factor receptor therapy erlotinib, which yielded a survival benefit in patients with advanced disease in combination with gemcitabine compared with gemcitabine alone, although this was a marginal incremental improvement for which the clinical significant has been heavily debated. More recently, the most significant therapeutic advance in PAC has come from the combination of several cytotoxic agents; infusional 5-FU, irinotecan and oxaliplatin. This combination chemotherapy regimen, known as FOLFIRINOX, improved survival in patients with an excellent functional status and stage IV disease by 4.3 months compared with gemcitabine alone. This improvement in survival did come at the cost expectedly of a significant increase in toxicities, including gastrointestinal and hematologic particularly. Other gemcitabine-based combination chemotherapy regimens including gemcitabine and platinum analogs and gemcitabine and capecitabine have consistently shown an increased response rate but no OS benefit in individual trials; albeit pooled and meta-analyses have indicated a survival benefit in good performance status patient for both these cytotoxic combinations. Accordingly, the 5-year survival for patients with PAC remains <5%, with an annual disease-specific mortality which approaches the incidence. The challenge remains therefore, to develop more effective systemic therapies against this challenging malignancy. Recent progress toward understanding the genetic events in the development of PAC, in combination with advances in the field of pharmacogenomics offer hope that we may build on achievements to-date to develop more effective therapeutic strategies for PAC in years to come.
    Preview · Article · Dec 2011 · The Pharmacogenomics Journal

Publication Stats

132 Citations
82.88 Total Impact Points

Institutions

  • 2010-2015
    • Memorial Sloan-Kettering Cancer Center
      • Department of Medicine
      New York, New York, United States
  • 2009-2015
    • Cornell University
      • Department of Medicine
      Итак, New York, United States