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  • 1
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    Abstracts
    Oxford University Press (OUP) ; 2012
    In:  Neuro-Oncology Vol. 14, No. suppl 3 ( 2012-09-01), p. iii1-iii94
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 14, No. suppl 3 ( 2012-09-01), p. iii1-iii94
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/nos183
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2012
    detail.hit.zdb_id: 2094060-9
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  • 2
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    Phase II study of mFOLFOX with bevacizumab (Bev) in metastatic gastroesophageal and gastric (GE) adenocarcinoma (AC).
    American Society of Clinical Oncology (ASCO) ; 2013
    In:  Journal of Clinical Oncology Vol. 31, No. 15_suppl ( 2013-05-20), p. 4084-4084
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 4084-4084
    Abstract: 4084 Background: The median survival for patients (pts) with metastatic GE AC in phase III studies is 〈 12 mos. Bev has demonstrated promising activity in metastatic GE AC when used in combination with cisplatin-based regimens in studies with patients from the Americas. We conducted a prospective phase II trial to investigate the efficacy of Bev in combination with mFOLFOX6 in pts with metastatic GE AC. Methods: Pts with previously untreated metastatic GE AC (gastric, GE junction, distal esophagus) received mFOLFOX6 (LV 400 mg/m 2 , 5-FU 400 mg/m 2 bolus and 2400 mg/m 2 over 46 hr continuous infusion, Ox 85 mg/m 2 ) and Bev 10 mg/kg q 2 wks. Response by RECIST was evaluated by CT q 8 wks. Primary objective was time to progression (TTP); secondary objectives were safety, response rate (RR), and overall survival (OS). Results: 39 pts were enrolled between 09/08 and 06/12. Pt characteristics are as follows: median age, 59 yo (range 27-79); M/F, 31/8; ECOG PS 0/1, 11/28; gastric/distal E and GEJ, 13/26; metastatic sites: lymph nodes 23, liver 19, lung 9, peritoneum 9; 〉 2 metastatic sites, 20; prior gastrectomy or esophagectomy, 7. Nine pts remain on study, and 15 pts are alive. Median # of cycles administered is 11 (range 4 - 〉 31). RR is 56.4% (4 CR, 18 PR). Median TTP is 8.2 mos. Median OS is 15.2 mos. Three pts survived 〉 24 mos. Grade 3/4 toxicities include neutropenia (13, 33.3%), neuropathy (8, 20.5%), DVT/PE (5, 12.8%), thrombocytopenia (3, 7.7%), anemia (1, 2.6%), hypertension (1, 2.6%), and proteinuria (1, 2.6%). We observed no GI perforations or grade 3/4 GI hemorrhagic events. Conclusions: FOLFOX6/Bev is well tolerated and associated with increased TTP and OS in pts with metastatic GE AC compared to historical data from similar populations treated without Bev. Our findings validate previous studies with Bev in combination with cisplatin-based regimens in pts from the Americas with metastatic GE AC. This study is supported by Genentech. Clinical trial information: NCT00673673.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2013.31.15_suppl.4084
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
    detail.hit.zdb_id: 2005181-5
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  • 3
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    Final analysis of a phase II study of Yale-modified FOLFIRINOX (mFOLFIRINOX) in metastatic pancreatic cancer (MPC).
    American Society of Clinical Oncology (ASCO) ; 2015
    In:  Journal of Clinical Oncology Vol. 33, No. 3_suppl ( 2015-01-20), p. 395-395
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 3_suppl ( 2015-01-20), p. 395-395
    Abstract: 395 Background: Although FOLFIRINOX is superior to gemcitabine in MPC, the regimen is associated with significant toxicities (Conroy et al. N Engl J Med 2011;364:1817). In our prior retrospective analysis, efficacy was not compromised by dose attenuations of FOLFIRINOX (Gunturu et al. Med Oncol 2013;30:361). Based on this analysis, a prospective phase II open label study to evaluate the efficacy and tolerability of mFOLFIRINOX in pts with locally advanced (LAPC) and MPC was conducted. Herein, we report the final analysis of the toxicity in LAPC and MPC, and the efficacy in MPC. Methods: Previously untreated pts with MPC or LAPC received mFOLFIRINOX every two wks with 25% dose reductions of irinotecan & bolus 5FU until progression, unacceptable toxicity, or surgical resection. All pts received prophylactic pegfilgrastim. CAT scans were obtained every 4 cycles for response assessment by RECIST. Toxicities in the entire cohort, and response rate (RR) & pt characteristics in the MPC cohort were compared to historical data reported by Conroy. PFS was determined for MPC cohort. Results: 31 pts with LAPC and 43 pts with MPC with ECOG PS 0/1 were enrolled between 11/11 and 01/14. Characteristics of evaluable (37/43) MPC pts were: med age, 61 yrs (range 50-76); male, 21; ECOG PS 0, 17; med # metastatic sites, 2; peritoneal disease, 14; biliary stent, 9; med # of cycles 10 (range 4-31). Grade 3/4 toxicities in entire cohort were: vomiting & peripheral neuropathy, 2.7%; ALT elevated, thromboembolism and febrile neutropenia, 4.1%; anemia, 5.4%; diarrhea,16.2% (no grade 4 diarrhea reported); neutropenia & fatigue, 12.2%; thrombocytopenia, 9.5%. Neutropenia (p 〈 0.0001), vomiting (p=0.0014), and fatigue (0.0194) were significantly decreased compared to historical data. RR in 37 pts with MPC was 35.1% (0 CR, 13 PR, 19 SD, 5 PD) and similar to historical data (36.9%; p 0.86). PFS in MPC pts was 6.11 mo with 95% CI (5.29, 8.31). Conclusions: mFOLFIRINOX with prophylactic pegfilgrastim in pts with MPC is associated with improved tolerability compared to full dose FOLFIRINOX, while RR and PFS in pts with MPC is similar to that reported by Conroy et all using full dose FOLFIRINOX. MPC pts are in follow-up for OS. Follow up for LAPC patients is ongoing. Clinical trial information: NCT01523457.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2015.33.3_suppl.395
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2015
    detail.hit.zdb_id: 2005181-5
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  • 4
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    Pathologic complete response (pCR) rates after neoadjuvant pertuzumab (P) and trastuzumab (H) administered concomitantly with weekly paclitaxel (T) and 5-fluorouracil/epirubicin/cyclophosphamide (FEC) chemotherapy for clinical stage I-III HER2-positive breast cancer.
    American Society of Clinical Oncology (ASCO) ; 2017
    In:  Journal of Clinical Oncology Vol. 35, No. 15_suppl ( 2017-05-20), p. 577-577
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. 577-577
    Abstract: 577 Background: Inclusion of H with chemotherapy has increased pathologic complete response (pCR) rates in HER2 positive breast cancer, and dual HER2 blockade involving H + P further increased efficacy. With dual HER2 blockade and taxane-based (+/-carboplatin followed by anthracycline) chemotherapies, pCR rates reach, 75% in estrogen receptor (ER) negative and 45% in ER+ patients. HER2 targeted therapies also increase the efficacy of anthracyclines but are not routinely combined due to potential cardiotoxicity. The goal of this phase II study was to assess pCR rate when H+P is administered during the entire treatment duration, including the anthracycline phase, of weekly T (80 mg/m 2 ) x 12 followed by FE(75 mg/m 2 )C x 4 neoadjuvant chemotherapy. Methods: pCR (ypT0/is and ypN0) rate was assessed separately in ER+ and ER- cancers following Simon’s two-stage design to detect improvement in pCR rates to 90% and 70% in the ER- and ER+ cohorts, respectively. Eligibility included age 〈 65, stage I-III, HER2+ disease, and normal cardiac function. Results: The ER- cohort completed full accrual of 25 patients: 23 completed therapy and surgery, 2 patients are still receiving treatment. The pCR rate is 78% (n=18, 95% CI:58-90%). The ER+ cohort was closed after 23 patients were accrued to the first stage due to lower than expected pCR of 26% (n=6, 95% CI:13-46%) at interim analysis. The incidence of grade 3/4 adverse events was 48% (n=24/50), the most common being neutropenia (n=12) and diarrhea (n=7). No patient experienced symptomatic congestive heart failure, one patient had a drop in LVEF to 〈 50% following completion of chemotherapy. Thirteen patients (27%) had a 〉 10% asymptomatic drop in their LVEF but remained above 50%, LVEF returned to baseline by the next assessment in half of these cases. Conclusions: Neoadjuvant P and H administered concomitantly with weekly T followed by FEC resulted in 78% pCR rate in ER-/HER2+ cancers. This pCR rate is among the highest reported in the literature. The pCR rate was substantially lower in ER+ cancers. Clinical trial information: NCT01855828.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2017.35.15_suppl.577
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
    detail.hit.zdb_id: 2005181-5
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  • 5
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    Disruption of HOX-PBX Interaction; a Potential Therapeutic Target in Leukemia.
    American Society of Hematology ; 2004
    In:  Blood Vol. 104, No. 11 ( 2004-11-16), p. 2057-2057
    Details
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 2057-2057
    Abstract: Most cases of acute myeloid leukemia (AML) are closely associated with gene rearrangements. Appraisal of these translocations and analysis of mouse models of leukemia has revealed that several members of the homeodomain containing family of transcription factors are implicated in the pathogenesis of leukemia. Overexpression of HOXA9 in murine models leads to the development of AML. This study focuses on the role of a subset of the HOX genes and their potential as a target for therapeutic intervention. We have designed a synthetic peptide, HXP4, that disrupts the interaction between HOX and PBX leading to growth inhibition of leukemic cells. An in vitro HOX-induced AML model of leukemia was utilised to determine the efficacy of HXP4 as a therapeutic agent. Using this immortalised cell line overexpressing HOXA9 (imHOXA9), we tested the efficacy of HXP4 in vitro. Cells were treated with HXP4 for four days and analysed. All results are expressed relative to untreated control cells. Following a 60μM dose of HXP4, no viable cells were detected as determined by trypan blue staining, suggesting that HXP4 was cytotoxic. Following treatment with a lower dose of 6μM HXP4, and re-suspension in drug-free medium for a further 6 days, cell regrowth was observed, suggesting a cytostatic effect. RT-PCR was performed to identify potential downstream targets of HXP4. Qualitative analysis showed other HOX family members to be unaffected by treatment with either HXP4 dose. A more detailed study was performed using quantitative RT-PCR with imHOXA9. Cells were treated with either 60μM HXP4, 3μM etoposide, or a combination of the two agents (H+Et) and harvested after 1, 2, and 4 hours. In general, no significant change in gene expression was observed in other HOX family members. However, HOXA1 was upregulated 3-fold when treated with HXP4, and HOXA2 was downregulated 2-fold in HXP4 and H+Et treated cells. The reasons for this are as yet unclear. HXP4 also downregulated N-RAS 3.5-fold at two hours. However, complete loss of N-RAS expression following H+Et treatment suggests that HXP4 may be more effective in combination with etoposide. CDC25 expression was slightly downregulated in HXP4-treated cells. The normal function of CDC25 is to activate CDC2 kinase in the nucleus, however in the absence of CDC25, CDC2 remains inactive leading to a delay in mitosis, supporting the proposed cytostatic mode of HXP4 action. For reasons as yet unclear, CD34 expression was upregulated 4-fold and 6-fold in HXP4 and H+Et treated cells respectively. These preliminary results suggest that HXP4 is a cytostatic agent at relatively low concentrations, with a reversible antiproliferative effect. Downstream genes regulated by disrupting the HOX-PBX interaction with HXP4 have been identified by RT-PCR, but microarray analysis will provide a more comprehensive screen for target genes. In vivo experiments are currently in progress. In conclusion blocking the interaction between HOX and PBX may represent a therapeutic strategy in leukemia treatment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V104.11.2057.2057
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 6
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    Voriconazole Is Safe and Effective as Prophylactic Antifungal Therapy Following Allogeneic Transplantation.
    American Society of Hematology ; 2004
    In:  Blood Vol. 104, No. 11 ( 2004-11-16), p. 5094-5094
    Details
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 5094-5094
    Abstract: Introduction: Despite fluconazole prophylaxis, invasive fungal disease (IFD) following allogeneic transplantation (alloBMT) remains problematic. Voriconazole is a second-generation triazole with activity against yeast and molds. Since FDA approval, voriconazole (VORI) has been used as antifungal prophylaxis in AlloBMT patients at UCSF Med Ctr. The goals of this retrospective study were to evaluate the incidence of IFD and to assess organ toxicity in alloBMT patients receiving VORI. Patients and Methods: The charts of 72 patients who received VORI as antifungal prophylaxis for alloBMT were reviewed. The mean age was 54 years (range 19–70), including 44 males and 28 females. Thirty-nine patients received reduced-intensity preparative therapy and 31 received myeloablative therapy. Thirty-six patients received stem cells from an HLA-identical relative, and 36 from an HLA-matched unrelated donor. All patients received tacrolimus, methotrexate +/− MMF for GVHD prophylaxis, G-CSF, acyclovir and antibacterial prophylaxis. Voriconazole (4 mg/kg) BID was administered from day −2 through day +100 post-transplant as tolerated. EORTC criteria were utilized to assess for IFD. Results: Two patients (3%) developed definitive IFD (mucor and aspergillus) and 3 patients (4%) had possible fungal infections. No cases of probable IFD were identified. Both patients with definitive IFD died, one from severe Grade IV GVHD and the other from sepsis and multiorgan failure. The patient with aspergillus had discontinued VORI & gt;1 month prior to IFI due to elevated liver tests (LFT’s). All the patients with possible IFD continued to receive VORI but received additional antimicrobial agents (i.e. caspofugin and antibacterials). One of these patients died from progressive pneumonia. Overall, voriconazole appeared well tolerated. Fifty-four of the 72 patients (75%) received VORI throughout transplant without interruption. Ten patients discontinued voriconazole within 30 days of alloBMT; increased LFT’s (n=7), prolonged QTc (n=2) and suspected new IFD (n=1). Four of the 10 patients were restarted on VORI and continued through day 100. Eight patients discontinued VORI after day 30 but before day 100; 2 planned taper, 1 died, 4 increased LFT’s and 1 for suspected IFD. Two of these patients restarted VORI. No significant cardiac toxicity was noted, despite a QTc of & gt;500 msec in 10 patients. The mean increase in QTc after initiating VORI was 34 msec (n=36). The median bilirubin, alk. phos and AST values post-transplant were 1.3 mg/dL, 134 U/L and 34 U/L, respectively. Eight patients developed severe hyperbilirubinemia ( & gt;6 mg/dL); 3 had VOD, 3 had GVHD. The mean peak creatinine was 1.5 mg/dL and four patients required hemodialysis. No severe or unexpected toxicity was noted. In addition, VORI increased serum tacrolimus levels necessitating a 60% reduction in standard tacrolimus dosing. The 100 and 180-day treatment related mortality rates in this study were 8% and 18%, respectively. Conclusions: In this cohort of 72 patients, VORI appears safe and effective as prophylaxis for alloBMT. A randomized trial comparing VORI to fluconazole as prophylaxis in alloBMT is currently ongoing. Recommendations regarding VORI administration in regards to QTc and LFT’s will be presented.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V104.11.5094.5094
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 7
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    The mutational profile of ER-, PR+, HER2- metastatic breast cancer.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 1025-1025
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 1025-1025
    Abstract: 1025 Background: ER-PR+Her2- breast cancer is a rare subtype occurring at approximately 1% of all breast carcinomas. Most of these cancers behave in an aggressive fashion with limited benefit from anti estrogen therapy, similar to triple negative breast cancer (TNBC). Better characterization of these tumors is needed for predicting clinical behavior, response to endocrine therapy, and eligibility for clinical trials. Here we sought to evaluate the mutational profile of a well curated set of ER-PR+HER2- metastatic breast cancers and compare to other receptor phenotypes. Methods: 2049 consecutive breast cancers submitted to Foundation Medicine for comprehensive genomic profiling (CGP) were included. ER, PR and HER2 expression were abstracted from submitted pathology reports. Cases without complete ER, PR and HER2 information in pathology reports were excluded. CGP was performed as previously described (Frampton, 2013). Results: Patient ages were similar across subgroups. Generally, ER-PR+HER2- tumors were rare (n = 23, 1.1%) and most similar to TNBC in their genomic profiles. These tumors harbored high rates of TP53 and BRCA1 alterations and low rates of PIK3CA, ESR1, and CDH1 alterations. Genomic loss of heterozygosity (gLOH) was similar in the ER-PR+HER2- and ER+PR+HER2-subtypes (8.18% and 8.66% respectively), and lower than TNBC (17.19%). Notably, a high rate of RB1 alterations were identified in the ER-PR+HER2- patients (13%, 3/23), numerically higher than the other subtypes. EGFR, MET, PTEN, CDKN2A and KRAS alterations were also observed at a higher frequency in ER-PR+Her2- cancers (8.7, 4.2, 39.1, 13.0 and 13.0% respectively) relative to the other subtypes. IO drug biomarkers including MSI, TMB and PD-L1 IHC were similar among the groups. Conclusions: The mutational profile for ER-PR+Her2- metastatic breast cancer more closely resembles TNBC than ER+ breast cancer. These data suggest molecular profiling may be a useful adjunct to optimize treatment strategies for this rare subset of cancers. Based on molecular characteristics, we recommend including ER-PR+Her2- patients in clinical trials for TNBC. Finally, genes including RB1, CKDN2A, PTEN, EGFR and MET are mutated at higher frequency in ER-PR+Her2- cancers than other subsets, suggesting unique biology with potential therapeutic implications. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.1025
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 8
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    Decreased HER2 expression in residual disease following neoadjuvant therapy in patients with HER2-positive breast cancer.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. e12621-e12621
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. e12621-e12621
    Abstract: e12621 Background: Human epidermal growth factor receptor-2 (HER2) overexpression is a defining feature of roughly 20% of localized breast cancer and represents a critical target for therapy. Since the demonstration that residual disease (RD) after neo adjuvant therapy (NAT) is associated with worse prognosis and that adjuvant ado trastuzumab emtansine (tDM1) improves survival, NAT has become the standard of care for localized HER2+ breast cancer. Retesting for HER2 overexpression post resection is variable, and data is conflicting regarding the prognostic significance of changes in HER2 expression pre and post therapy. The objective of this study was to evaluate the association of pre and post neo adjuvant therapy HER2 immunohistochemistry (IHC) expression on breast cancer outcomes in our institutional database. Methods: After IRB approval, data was gathered for patients with localized HER2+ breast cancer receiving NAT including trastuzumab/pertuzumab at Yale Cancer Center between 2012 and 2022. Pathologic complete response (pCR) was defined as no residual invasive tumor in breast and lymph nodes. Patients were divided into 3 cohorts by response and HER2 IHC: Cohort 1 pCR Cohort 2 pre-treatment 3+/post treatment 1-2+, and Cohort 3 pre-treatment 3+/post treatment 3+. A Kaplan-Meier survival analysis was done to assess recurrence free survival at 36 months. Results: Within the specified time interval, we identified 104 patients with localized HER2-IHC 3+ breast cancer who received neoadjuvant therapy. The pCR rate was 62.5% (65/104), while 37.5% (39/104) of patients had RD. Among patients with RD, 58.9% (23/39) remained HER2 IHC 3+ and 41% (16/39) had decreased HER2 expression IHC1+/IHC 2+. Median follow-up was 27.9 months at time of analysis. In patients with HER2 3+ RD 26% (6/23) developed local recurrence or distant metastasis while none of patients with HER2 IHC 1+ or 2+ RD had relapse ( p= 0.0309). In patients with pCR, 6.15% (4/65) had recurrence. Kaplan-Meier survival analysis showed a significant difference between the 3 groups (log rank p= 0.004). Conclusions: In our retrospective cohort, decreased HER2 expression by IHC following neoadjuvant treatment was associated with lower recurrence rates. If confirmed, RD HER2 IHC expression could be used as a prognostic biomarker to select patients for more or less aggressive adjuvant therapy, stratify patients in adjuvant trials, and identify patients who may benefit from more intensive post therapy surveillance.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.e12621
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 9
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    Metastatic breast cancer (MBC) with ultra-high tumor mutational burden (UHTMB): A comprehensive genomic profiling (CGP) study.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 1036-1036
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 1036-1036
    Abstract: 1036 Background: Pts with MBC whose tumors feature high TMB (≥ 10 mutations/Mb) are eligible for on label immune checkpoint inhibitor (ICI) treatment. This study evaluated the genomic landscape of MBC with “Ultra high” TMB, defined at 〉 20 mutations/Mb. Methods: 2049 MBC underwent hybrid capture-based CGP to evaluate all classes of genomic alterations (GA), TMB, microsatellite instability (MSI) and trinucleotide mutational signatures. HER2 IHC results were available in a subset of pts. PD-L1 expression on immunocytes was determined by IHC (Ventana SP142). Results: 45/2049 (2.2%) of MBC were UHTMB. 45 (100%) pts had metastatic disease. 38 (84%) had documented Stage IV disease and 7 documented axillary LN metastases at the time of sequencing. Local breast tumor was used for CGP in 19 (42.2%) MBC and metastatic site biopsy was used in 26 (57.8%). When compared with 2004 non-UHTMB pts with UHTMB were older (mean 64.6 yrs vs 58.2 yrs p 〈 .0001), more often had lobular histology (40.0% vs 14.5% p 〈 .0001) and ER+ disease (86.6% vs 70.0%). Of the 35 UHTMB cases with HER2 IHC data available, 11 (31.4%%) were HER2 IHC negative (0+), 21 (60.0%) were HER2-low status (9 1+ and 12 2+/ISH negative) and 3 (8.6%) were HER2 IHC positive (3+). 1/3 HER2 IHC2+ cases and 2/45 (4.4%) of all UHTMB cases were positive for HER2 copy number gain on CGP. UHTMB cases had more driver GA/tumor (mean 9.8 vs 5.7 p 〈 .0001) and were less often TNBC (13.3% vs 27.0% p = .041) compared to non-UHTMB high cancers. Mutation signature analysis revealed APOBEC was predominant in UHTMB samples (82.5%); MMR signature was also observed in 10% of cases. MSI high status was significantly more frequent in UHTMB high cases (11.6% vs 0.4% p 〈 .0001). GA more frequently identified in UHTMB cases included CDH1 (45.5% vs 14.3% p 〈 .0001), PIK3CA (81.8% vs 37.9% p 〈 .0001), CDKN2A (11.4% vs 3.2% p = .017), ARID1A (25.0% vs 5.0% p 〈 .0001) and NF1 (20.5% vs 5.9% p = .0014). PD-L1 ( CD274) gene amplification (2.3% vs 1.3%) or protein expression by the Ventana SP142 assay (57.14% vs 51.10%) were not significantly different among groups. Conclusions: UHTMB MBC is a rare, yet clinically important subset of clinically advanced breast cancer driven by APOBEC mutagenesis, with high incidence of ER+ lobular histology and frequent alterations in CDH1 and PIK3CA. In addition to potential benefit from ICI based treatment, UHTMB MBC present with a high frequency of HER2-low status which may impact therapy decisions for this rare disease. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.1036
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 10
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    Mapping the Genetic Landscape of Human Cells
    Elsevier BV ; 2018
    In:  Cell Vol. 174, No. 4 ( 2018-08), p. 953-967.e22
    Details
    In: Cell, Elsevier BV, Vol. 174, No. 4 ( 2018-08), p. 953-967.e22
    Type of Medium: Online Resource
    ISSN: 0092-8674
    URL: Article
    DOI: 10.1016/j.cell.2018.06.010
    RVK:
    XA 36269
    RVK:
    WA 15000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2018
    detail.hit.zdb_id: 187009-9
    detail.hit.zdb_id: 2001951-8
    SSG: 12
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