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  • American Association for Cancer Research (AACR)  (6)
  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. P4-17-08-P4-17-08
    Abstract: Background: The clinical utility of routine annual mammogram after curative-intent treatment for male breast cancer is uncertain. There is potentially greater value after lumpectomy (as surveillance for ipsilateral recurrence) than mastectomy (as screening for a new contralateral cancer). The goal of this study was to assess real world use of mammography in men during the first year after lumpectomy or mastectomy to treat breast cancer. Methods: Administrative claims data from OptumLabs Data Warehouse (a large US database that includes privately insured patients and Medicare Advantage-insured enrollees from all 50 states and of all ages and ethnic and racial groups) were used to identify men treated with breast surgery for a new diagnosis of breast cancer between 2007 and 2017. We required continuous coverage starting at least 6 months prior to the non-metastatic breast cancer diagnosis and continuing until at least 13 months after the breast surgery. Our primary endpoint was the proportion of patients who had at least one mammogram during the year (13-month period, to allow for scheduling and other logistical delays) after lumpectomy or mastectomy. Univariate and multivariate testing were performed to identify predictors of mammography (with p & lt;0.05 used as the threshold for statistical significance for both). Our secondary endpoint was the proportion with at least one mammogram within 24 months of surgery, performed in a subset who maintained their insurance coverage for at least that duration. Results: The 13-month analysis included 730 men with a median age at diagnosis of 62 years (Range: 25 to 87 years) and a median follow-up duration of 35 months (Range: 13 to 134 months). 209 (29%) of these men underwent mammography within 13 months after surgery. The characteristics of patients who underwent mammography and those who did not are shown in Table 1. Mammography was more likely after lumpectomy than mastectomy (41% vs. 27%) and after radiation therapy (41% vs. 32% in those who did not receive radiation). In a multivariate logistic regression model, more recent diagnosis (2015+) was associated with lower odds of undergoing mammography, while receipt of radiation was associated with higher odds of undergoing mammography. In the subset of patients with two or more years of post-surgery coverage (n=527), the proportion who had at least one mammogram during that 24-month period was 49% after lumpectomy and 40% after mastectomy. Conclusions: In this insured cohort, 73% of men did not undergo mammography within a year after mastectomy, and 59% did not within a year after lumpectomy. Mammography was less likely in patients diagnosed more recently (perhaps due to acknowledgment of the unique aspects of male breast cancer including a relatively low risk of contralateral second primary tumors), and more likely in those who received radiation. These variations in practice likely result from the paucity of evidence-based guidelines for male breast cancer survivorship care. More research is needed pertaining to whether or not mammograms improve clinical outcomes after curative intent treatment for male breast cancer. Table 1: Patient characteristics associated with receipt of mammogram within first 13 months after male breast cancer surgeryUnivariate AnalysisMultivariate AnalysisNo Mammogram (N=521)Mammogram (N=209)P-value, chi-square testOdds Ratio (OR) and 95% CIP-value for ORAge Group:0.1225-4966 (12.7%)32 (15.3%)Reference50-64216 (41.5%)98 (46.9%)0.99 (0.60, 1.63)0.9665-74112 (21.5%)44 (21.1%)0.87 (0.48, 1.57)0.6575+127 (24.4%)35 (16.7%)0.57 (0.30, 1.07)0.08Census Region:0.52Midwest138 (26.5%)59 (28.2%)ReferenceNortheast97 (18.6%)47 (22.5%)1.10 (0.68, 1.78)0.69South223 (42.8%)79 (37.8%)0.74 (0.49, 1.11)0.15West63 (12.1%)24 (11.5%)0.83 (0.47, 1.47)0.51Year of diagnosis:0.072007-2010126 (24.2%)65 (31.1%)Reference2011-2014199 (38.2%)82 (39.2%)0.80 (0.54, 1.20)0.292015+196 (37.6%)62 (29.7%)0.63 (0.41, 0.96)0.03Elixhauser Category:0.250148 (28.4%)69 (33.0%)Reference1-2218 (41.8%)74 (35.4%)0.85 (0.56, 1.28)0.433+155 (29.8%)66 (31.6%)1.18 (0.75, 1.87)0.47Surgery Type:0.005Lumpectomy55 (10.6%)38 (18.2%)ReferenceMastectomy466 (89.4%)171 (81.8%)1.57 (0.97, 2.55)0.07Chemotherapy:0.79No301 (57.8%)123 (58.9%)ReferenceYes220 (42.2%)86 (41.1%)0.79 (0.54, 1.16)0.23Radiation:0.02No355 (68.1%)124 (59.3%)ReferenceYes166 (31.9%)85 (40.7%)1.51 (1.03, 2.20)0.03 Citation Format: Siddhartha Yadav, Lindsey Sangaralingham, Stephanie R. Payne, Karthik V. Giridhar, Tina J. Hieken, Judy C. Boughey, Robert W. Mutter, John R. Hawse, Rafael E. Jimenez, Rachel A. Freedman, Sadia Choudhery, Fergus J. Couch, Celine M. Vachon, Nilay Shah, Roberto A. Leon-Ferre, Kathryn J. Ruddy. Surveillance mammography after treatment for male breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-17-08.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 2
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 10, No. 4 ( 2020-04-01), p. 568-587
    Abstract: Disease recurrence causes significant mortality in B-progenitor acute lymphoblastic leukemia (B-ALL). Genomic analysis of matched diagnosis and relapse samples shows relapse often arising from minor diagnosis subclones. However, why therapy eradicates some subclones while others survive and progress to relapse remains obscure. Elucidation of mechanisms underlying these differing fates requires functional analysis of isolated subclones. Here, large-scale limiting dilution xenografting of diagnosis and relapse samples, combined with targeted sequencing, identified and isolated minor diagnosis subclones that initiate an evolutionary trajectory toward relapse [termed diagnosis Relapse Initiating clones (dRI)]. Compared with other diagnosis subclones, dRIs were drug-tolerant with distinct engraftment and metabolic properties. Transcriptionally, dRIs displayed enrichment for chromatin remodeling, mitochondrial metabolism, proteostasis programs, and an increase in stemness pathways. The isolation and characterization of dRI subclones reveals new avenues for eradicating dRI cells by targeting their distinct metabolic and transcriptional pathways before further evolution renders them fully therapy-resistant. Significance: Isolation and characterization of subclones from diagnosis samples of patients with B-ALL who relapsed showed that relapse-fated subclones had increased drug tolerance and distinct metabolic and survival transcriptional programs compared with other diagnosis subclones. This study provides strategies to identify and target clinically relevant subclones before further evolution toward relapse. See related video: https://vimeo.com/442838617 See related article by E. Waanders et al .
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 3
    In: Blood Cancer Discovery, American Association for Cancer Research (AACR), Vol. 1, No. 1 ( 2020-07-01), p. 96-111
    Abstract: Relapse of acute lymphoblastic leukemia (ALL) remains a leading cause of childhood cancer-related death. Prior studies have shown clonal mutations at relapse often arise from relapse-fated subclones that exist at diagnosis. However, the genomic landscape, evolutionary trajectories, and mutational mechanisms driving relapse are incompletely understood. In an analysis of 92 cases of relapsed childhood ALL incorporating multimodal DNA and RNA sequencing, deep digital mutational tracking, and xenografting to formally define clonal structure, we identified 50 significant targets of mutation with distinct patterns of mutational acquisition or enrichment. CREBBP, NOTCH1, and RAS signaling mutations arose from diagnosis subclones, whereas variants in NCOR2, USH2A, and NT5C2 were exclusively observed at relapse. Evolutionary modeling and xenografting demonstrated that relapse-fated clones were minor (50%), major (27%), or multiclonal (18%) at diagnosis. Putative second leukemias, including those with lineage shift, were shown to most commonly represent relapse from an ancestral clone rather than a truly independent second primary leukemia. A subset of leukemias prone to repeated relapse exhibited hypermutation driven by at least three distinct mutational processes, resulting in heightened neoepitope burden and potential vulnerability to immunotherapy. Finally, relapse-driving sequence mutations were detected prior to relapse using droplet digital PCR at levels comparable with orthogonal approaches to monitor levels of measurable residual disease. These results provide a genomic framework to anticipate and circumvent relapse by earlier detection and targeting of relapse-fated clones. Significance: This study defines the landscape of mutations that preexist and arise after commencement of ALL therapy and shows that relapse may be propagated from ancestral, major, or minor clones at initial diagnosis. A subset of cases exhibits hypermutation that results in expression of neoepitopes that may be substrates for immunotherapeutic intervention. See related video: https://vimeo.com/442838617 See related commentary by Ogawa, p. 21. See related article by S. Dobson et al . This article is highlighted in the In This Issue feature, p. 5
    Type of Medium: Online Resource
    ISSN: 2643-3249 , 2643-3230
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 4
    In: Blood Cancer Discovery, American Association for Cancer Research (AACR), Vol. 1, No. 1 ( 2020-07), p. 96-111
    Type of Medium: Online Resource
    ISSN: 2643-3230 , 2643-3249
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 5
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 18, No. 10_Supplement ( 2020-10-01), p. B27-B27
    Abstract: Colorectal cancer (CRC) is a leading cause of cancer-related death. PIK3CA mutations are common, leading to a constitutively active phosphoinositide-3 kinase (PI3K). An effective means to target this pathway has yet to be identified. We investigated the use of a panel of inhibitors targeting the PI3K pathway including copanlisib (dual PI3K/mTOR), BYL-719 (alpha isomer specific PI3K), GDC-0941 (pan PI3K), and TAK-228 (MTORC1/2). To test the efficacy of these inhibitors in CRC, murine organotypic cancer spheroids (MDOCS) were generated from the invasive adenocarcinomas of Apc and Pik3ca transgenic mice. These inhibitors were investigated at clinically relevant doses (100-400nM). Copanlisib and TAK-228 were the only inhibitors to result in a significant reduction in the size of the MDOCS (200nM; 27% p-value & lt;0.001, 18% p-value & lt;0.001, respectively). This result correlated with a decrease in the phosphorylation of AKT (ser473), RPS6, and 4EBP1. Minimal induction of apoptosis was observed using these inhibitors alone as measured by cleaved PARP and cleaved caspase 3. These results were confirmed in vivo using transgenic mice with TAK-228 (1mg/kg/day) and copanlisib (10mg/kg q2d x5) resulting in a reduction in lumen occlusion of the colon tumors. Persistent BCL-2 and BCL-xL signaling was hypothesized to be preventing the induction of apoptosis. To determine if inhibition of these BCL-2 family members would further sensitize these MDOCS to copanlisib and TAK-228, these inhibitors were tested in combination with navitoclax (ABT-263; BCL-2 family inhibitor). A dramatic enhanced sensitivity was observed in MDOCS (30% p-value & lt;0.001, 23% p-value & lt;0.001, respectively). This correlated with an induction of apoptosis as measured by cleaved caspase 3. Next a panel of eight CRC patient-derived organotypic cancer spheroids (PDOCS) were treated with the combination of TAK-228 and navitoclax. Differential sensitivity was observed across the panel (25% resistant, 37.5% intermediate, and 37.5% highly sensitive) owing to the importance of mutational profile with targeted therapies. These studies indicate the benefit of MTORC1/2 for the treatment of PIK3CA mutant CRC and with enhanced activity of the combination of MTORC1/2 inhibition in combination with BCL-2 family inhibition. These therapies deserve further investigation for the treatment of patients with PIK3CA mutant CRC. Citation Format: Rebecca A. DeStefanis, Susan N. Payne, Devon Miller, Cheri A. Pasch, Christopher Babiarz, Alyssa DeZeeuw, Stephanie L. Fricke, Carley Sprackling, Alexander E. Yueh, Demetra P. Korkos, Dana R. Van De Hey, Gioia Sha, Aurora Greane, Jeremy D. Kratz, Linda Clipson, Kristina A. Matkowskyj, Michael A. Newton, Dustin A. Deming. MTORC1/2 inhibition as a treatment strategy for PIK3CA mutant colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B27.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 6
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 18, No. 2 ( 2019-02-01), p. 346-355
    Abstract: PIK3CA mutations are common in clinical molecular profiling, yet an effective means to target these cancers has yet to be developed. MTORC1 inhibitors are often used off-label for patients with PIK3CA mutant cancers with only limited data to support this approach. Here we describe a cohort of patients treated with cancers possessing mutations activating the PI3K signaling cascade with minimal benefit to treatment with the MTORC1 inhibitor everolimus. Previously, we demonstrated that dual PI3K/mTOR inhibition could decrease proliferation, induce differentiation, and result in a treatment response in APC and PIK3CA mutant colorectal cancer. However, reactivation of AKT was identified, indicating that the majority of the benefit may be secondary to MTORC1/2 inhibition. TAK-228, an MTORC1/2 inhibitor, was compared with dual PI3K/mTOR inhibition using BEZ235 in murine colorectal cancer spheroids. A reduction in spheroid size was observed with TAK-228 and BEZ235 (−13% and −14%, respectively) compared with an increase of & gt;200% in control (P & lt; 0.001). These spheroids were resistant to MTORC1 inhibition. In transgenic mice possessing Pik3ca and Apc mutations, BEZ235 and TAK-228 resulted in a median reduction in colon tumor size of 19% and 20%, respectively, with control tumors having a median increase of 18% (P = 0.02 and 0.004, respectively). This response correlated with a decrease in the phosphorylation of 4EBP1 and RPS6. MTORC1/2 inhibition is sufficient to overcome resistance to everolimus and induce a treatment response in PIK3CA mutant colorectal cancers and deserves investigation in clinical trials and in future combination regimens.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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