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  • 1
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    Concordance of Genomic Alterations between Primary and Recurrent Breast Cancer
    American Association for Cancer Research (AACR) ; 2014
    In:  Molecular Cancer Therapeutics Vol. 13, No. 5 ( 2014-05-01), p. 1382-1389
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 13, No. 5 ( 2014-05-01), p. 1382-1389
    Abstract: There is growing interest in delivering genomically informed cancer therapy. Our aim was to determine the concordance of genomic alterations between primary and recurrent breast cancer. Targeted next-generation sequencing was performed on formalin-fixed paraffin-embedded (FFPE) samples, profiling 3,320 exons of 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer. Point mutations, indels, copy-number alterations (CNA), and select rearrangements were assessed in 74 tumors from 43 patients (36 primary and 38 recurrence/metastases). Alterations potentially targetable with established or investigational therapeutics were considered “actionable.” Alterations were detected in 55 genes (mean 3.95 alterations/sample, range 1–12), including mutations in PIK3CA, TP53, ARID1A, PTEN, AKT1, NF1, FBXW7, and FGFR3 and amplifications in MCL1, CCND1, FGFR1, MYC, IGF1R, MDM2, MDM4, AKT3, CDK4, and AKT2. In 33 matched primary and recurrent tumors, 97 of 112 (86.6%) somatic mutations were concordant. Of identified CNAs, 136 of 159 (85.5%) were concordant: 37 (23.3%) were concordant, but below the reporting threshold in one of the matched samples, and 23 (14.5%) discordant. There was an increased frequency of CDK4/MDM2 amplifications in recurrences, as well as gains and losses of other actionable alterations. Forty of 43 (93%) patients had actionable alterations that could inform targeted treatment options. In conclusion, deep genomic profiling of cancer-related genes reveals potentially actionable alterations in most patients with breast cancer. Overall there was high concordance between primary and recurrent tumors. Analysis of recurrent tumors before treatment may provide additional insights, as both gains and losses of targets are observed. Mol Cancer Ther; 13(5); 1382–9. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-13-0482
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 2
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    PI3K Pathway Mutations and PTEN Levels in Primary and Metastatic Breast Cancer
    American Association for Cancer Research (AACR) ; 2011
    In:  Molecular Cancer Therapeutics Vol. 10, No. 6 ( 2011-06-01), p. 1093-1101
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 10, No. 6 ( 2011-06-01), p. 1093-1101
    Abstract: The purpose of this work was to determine whether there are differences in PIK3CA mutation status and PTEN protein expression between primary and matched metastatic breast tumors as this could influence patient management. Paraffin sections of 50 μm were used for DNA extraction and slides of 3 μm for immunohistochemistry (IHC) and FISH. Estrogen receptor, progesterone receptor, and HER2 IHC were repeated in a central laboratory for both primary tumors and metastases. PTEN levels were assessed by IHC and phosphoinositide 3-kinase (PI3K) pathway mutations were detected by a mass spectroscopy–based approach. Median age was 48 years (range: 30–83 years). Tumor subtype included 72% hormone receptor positive/HER2 negative, 20% HER2-positive, and less than 7.8% triple receptor negative. Tissues were available for PTEN IHC in 46 primary tumors and 52 metastases. PTEN was lost in 14 (30%) primary tumors and 13 (25%) metastases. There were five cases of PTEN loss and eight cases of PTEN gain from primary tumors to metastases (26% discordance). Adequate DNA was obtained from 46 primary tumors and from 50 metastases for PIK3CA analysis. PIK3CA mutations were detected in 19 (40%) of primary tumors and 21 (42%) of metastases. There were five cases of PIK3CA mutation loss and four cases of mutation gain (18% discordance). There was an increase of the level of PIK3CA mutations in four cases and decrease in one case from primary tumors to metastases. There is a high level of discordance in PTEN level, PIK3CA mutations, and receptor status between primary tumors and metastases that may influence patient selection and response to PI3K-targeted therapies. Mol Cancer Ther; 10(6); 1093–101. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-10-1089
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 3
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    Genomic alterations driving breast cancer (BC) metastases and their relationship with the subtype switch in the GEICAM ConvertHER study.
    American Society of Clinical Oncology (ASCO) ; 2017
    In:  Journal of Clinical Oncology Vol. 35, No. 15_suppl ( 2017-05-20), p. 1017-1017
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. 1017-1017
    Abstract: 1017 Background: To understand the mechanisms underlying the evolution of tumors in the process of metastasis, we studied 61 paired primary-relapse BC from the GEICAM ConvertHER study. While some of the metastases maintained the clinical (ER/PR and HER2 status) and/or intrinsic subtype (defined by expression arrays) of the original tumor (concordant), others exhibited a subtype shift (discordant). We aimed to identify the genomic alterations driving the metastases and, particularly, their relationship with the subtype switch. Methods: We detected the somatic variants (mutations and copy number alterations (CNAs)) affecting 202 genes across the 61 sample pairs via targeted sequencing. We employed the Cancer Genome Interpreter (cancergenomeinterpreter.org), a bioinformatics approach to identify the alterations most likely driving tumorigenesis, and subsequently identified those whose cancer cell fraction markedly changed in the metastases. We explored the clonal remodeling in metastasis comparing the cell fractions of driver mutations in both concordant and discordant tumors. Results: We found that 156 genes had 747 somatic mutations and 171 genes suffered 1042 somatic CNAs in the 61 studied tumor pairs. We identified a median of 11 and 9 mutations in primaries and metastases, respectively. Several frequent BC mutational drivers, such as TP53, PIK3CA, MLL3, MAP3K1, and NOTCH2 were amongst the more frequently changed their cancer cell fraction in metastases with respect to primaries. We found that driver mutations of discordant tumors exhibited a significantly higher increase of clonal cell fraction. Moreover, whether the clonal status of a driver mutation was conserved in the metastasis was significantly associated to whether the tumor maintains its clinical subtype but not its intrinsic subtype. Conclusions: Our results suggest that a shift in the clinical subtype of BC undergoing metastasis is accompanied by more significant changes at the genomic level than those suffered by tumors that maintain their clinical subtype. This remodeling of the landscape of drivers could open new therapeutic opportunities to specifically target discordant BC.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2017.35.15_suppl.1017
    RVK:
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    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
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  • 4
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    Dynamic clonal remodelling in breast cancer metastases is associated with subtype conversion
    Elsevier BV ; 2019
    In:  European Journal of Cancer Vol. 120 ( 2019-10), p. 54-64
    Details
    In: European Journal of Cancer, Elsevier BV, Vol. 120 ( 2019-10), p. 54-64
    Type of Medium: Online Resource
    ISSN: 0959-8049
    URL: Article
    DOI: 10.1016/j.ejca.2019.07.003
    RVK:
    XA 42017.A
    RVK:
    XA 42017
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2019
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  • 5
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    Cancer gene profile of metastatic breast cancer.
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 15_suppl ( 2012-05-20), p. 1015-1015
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 1015-1015
    Abstract: 1015 Background: There is great interest in using genomic information to guide therapy selection in cancer patients. The aim of this study was to determine the spectrum of genomic alterations identified in MBC patients, and evaluate the concordance of alterations between primary and recurrent tumors. Methods: We performed comprehensive profiling on formalin-fixed paraffin embedded samples from 42 patients with MBC using a targeted next generation sequencing (NGS) assay in a CLIA laboratory (Foundation Medicine). Genomic libraries were captured for 3,230 exons in 182 cancer related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to an average depth of 390X with 99% of bases covered 〉 100X. In total 30 primary and 37 recurrent tumors were profiled, including 3 separate recurrences in 1 patient and matched primary-recurrences in 22 patients. Point mutations, indels, copy number alterations and rearrangements were assessed. Alterations that are targetable with established or investigational therapeutics were considered “actionable”. Results: At least 1 genomic alteration was identified in all but 2 breast samples (both primary tumors). Point mutations were identified in several cancer-related genes including PIK3CA, TP53, PTEN, CDH1, ARID1A, AKT1, NF1, FBXW7 and FGFR3. Amplification was observed in HER2; 11 of 12 HER2 IHC positive samples were found to have HER2 gains by NGS; in addition, a HER2 gain was identified by NGS in a HER2- (1+ IHC) sample. Amplification of PIK3CA, IGF1R, FGFR2, AKT2, MDM2, and MCL1 plus a CDKN2A homozygous deletion were also identified. While the majority of known driver alterations (85%) were concordant in the matched pairs of primary and recurrent tumors, in 11 of 22 sets there was at least 1 discordant driver alteration, and these included both gains and losses of potential therapeutic targets. Overall 32 of 42 patients (76%) had an actionable genomic alteration. Conclusions: Genomic profiling of breast cancer samples reveals genomic alterations in most metastatic breast cancer patients. Over three quarters of patients have actionable findings, suggesting that genomic profiling may assist in individualized pathway-directed therapy.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.15_suppl.1015
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
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  • 6
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    Abstract LB-231: Phase Ib dose escalation and biomarker study of MK2206 in combination with standard doses of weekly paclitaxel in patients with locally advanced or metastatic solid tumors with expansion in advanced breast cancer
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. LB-231-LB-231
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. LB-231-LB-231
    Abstract: Background: AKT protein kinase is activated in a large proportion of human solid tumors. Increased levels of AKT phosphorylation and PTEN loss predict poor outcome. Synergistic or additive inhibitory effects have been observed on proliferation/viability of breast cancer cell lines when MK2206, allosteric inhibitor of AKT, is given in combination with taxanes. Primary goals: determine the maximum tolerated dose (MTD) of the combination of MK2206 and weekly paclitaxel and to determine safety and activity of the combination in metastatic breast cancer. Secondary objectives included pharmacokinetics (PK), pharmacodynamic (PD) studies in tissue and blood, and toxicity. Methods: Phase Ib 3+3 dose escalation study. Patients were treated using continuous weekly dosing. A fixed dose of paclitaxel was given at 80mg/m2 weekly on day 1, followed by MK2206 PO on day 2. During dose escalation: MK2206 was escalated using 3 levels: 90mg, 135mg, 200mg. For expansion: MK2206 was given at the MTD of 200mg po. Treatment was continued until tumor progression, excessive toxicity, or patient (pt) request. Blood was collected for PK and PD markers as scheduled. Sequential tumor biopsies were completed in most patients. A cycle consisted of 3 weeks of therapy and DLT was defined as unacceptable toxicity occurring during the first cycle. Results: 23 patients were treated, 9 in the dose escalation and 14 in the dose expansion. Four patients were replaced at dose expansion due to lack of compliance, early progression or intolerance at first dose (2 of these pts were included in the toxicity analysis). Median age was 55 years, 4 male and 19 female. Dose escalation was completed with no DLT. CTCAE Grade ≥3 adverse events were G3 fatigue (2/9 pts), and G3 rash (1/9 pts), and G3 nail infection (1/9 pts). CTCAE in expansion phase will be reported and included G3/4 rash in at least 4 patients requiring MK2206 dose reduction to 135mg weekly. Based on this, phase II recommended dose was established as paclitaxel 80mg/m2 weekly on day 1, and MK2206 135mg weekly on day 2. Observed clinical activity in the dose escalation included: objective responses in pts with a metastatic breast and a metastatic colon cancers, and stable disease over 15 weeks in 2 pts with ocular melanomas, 1 squamous cell carcinoma of the head and neck and 1 ovarian cancer. Expansion cohort clinical activity will be reported. Baseline molecular testing revealed PTEN low/loss in a pt with colon cancer (best and longest response), and a pt with head and neck cancer (on therapy for 25 weeks). Conclusion: Combined paclitaxel and MK2206 were well tolerated. There was clinical activity in the dose escalation, with PTEN low/loss noted in some patients with prolonged SD or PR. Complete report on dose expansion, molecular correlates will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-231. doi:1538-7445.AM2012-LB-231
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-LB-231
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 7
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    Abstract LB-37: P-REX1 is a novel PTEN-interacting protein that activates PI3K signaling in breast cancer.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. LB-37-LB-37
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. LB-37-LB-37
    Abstract: The mechanism(s) underlying regulation of the tumor suppressor phosphatase PTEN, which negatively regulates phosphatidylinositol 3-kinase (PI3K) signaling, remains unclear. The PI3K/AKT pathway regulates cancer cell growth, survival, and metabolism. Since PTEN is expressed and PI3K is hyperactivated in the majority of breast cancers, we hypothesized that PTEN is inhibited by protein interactions, thus derepressing PI3K signaling. A proteomic screen to identify novel PTEN-binding proteins in breast cancer cells revealed interaction with P-REX1, a known Rac guanine exchange factor (GEF). A separate proteomic experiment to identify PTEN/PI3K-regulated proteins showed that P-REX1 levels are decreased upon loss of PTEN and increased upon inhibition of PI3K. PTEN/P-REX1 interaction and the effects of pharmacological PI3K pathway inhibitors on P-REX1 levels were validated by immunoprecipitation/immunoblot analyses. In reverse-phase protein array analysis of lysates from 597 primary human breast tumors, levels of P-REX1 protein were positively correlated with PTEN protein, and inversely correlated with phospho-AKT-T308 (both p & lt;0.005). Comparing diverse types of carcinomas (n=2,009 from International Genomics Consortium's expO) and cancer cell lines (n=807 from Cancer Cell Line Encyclopedia), PREX1 mRNA levels were highest in ER+ and HER2+ breast cancer. In another series of 1,293 epithelial tumors (from The Cancer Genome Atlas), PREX1 is amplified or mutated in 6.2% of cases, and in 5% of breast cancers. Since multiple genomic lesions that can activate the PI3K pathway are known to co-exist in cancer cells, we tested whether PREX1 lesions co-exist with other PI3K pathway-activating lesions. Among genes encoding proteins implicated in growth factor receptor/PI3K/PTEN signaling and phosphatidylinositol metabolism, we found a significant enrichment for PREX1 mutation/amplification in 54/79 (68%) genes across 1,523 carcinomas. Overexpression and RNAi knockdown experiments revealed that P-REX1 increases steady-state and insulin-like growth factor-1 (IGF-1)-induced PI3K-dependent AKT phosphorylation in ER+ breast cancer cells. Studies are underway to identify the mechanistic role of P-REX1 in PI3K/PTEN signaling, and to determine whether P-REX1 directly inhibits PTEN. Our findings suggest that 1) P-REX1 is an activator of the PI3K/AKT pathway, 2) expression and mutation patterns implicate PREX1 in PI3K activation, and 3) neutralizing P-REX1 effects on PTEN/PI3K may be a novel therapeutic approach to selectively abrogate PI3K signaling in ER+ and HER2+ breast cancers while sparing normal tissues. Citation Format: Lloye M. Dillon, Jennifer R. Bean, Justin M. Balko, W. Hayes McDonald, David B. Friedman, Ana M. Gonzalez-Angulo, Gordon B. Mills, Carlos L. Arteaga, Todd W. Miller. P-REX1 is a novel PTEN-interacting protein that activates PI3K signaling in breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Canc er Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-37. doi:10.1158/1538-7445.AM2013-LB-37
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-LB-37
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 8
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    ERα-Dependent E2F Transcription Can Mediate Resistance to Estrogen Deprivation in Human Breast Cancer
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Discovery Vol. 1, No. 4 ( 2011-09-01), p. 338-351
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 1, No. 4 ( 2011-09-01), p. 338-351
    Abstract: Most estrogen receptor α (ER)-positive breast cancers initially respond to antiestrogens, but many eventually become estrogen-independent and recur. We identified an estrogen-independent role for ER and the CDK4/Rb/E2F transcriptional axis in the hormone-independent growth of breast cancer cells. ER downregulation with fulvestrant or small interfering RNA (siRNA) inhibited estrogen-independent growth. Chromatin immunoprecipitation identified ER genomic binding activity in estrogen-deprived cells and primary breast tumors treated with aromatase inhibitors. Gene expression profiling revealed an estrogen-independent, ER/E2F-directed transcriptional program. An E2F activation gene signature correlated with a lesser response to aromatase inhibitors in patients' tumors. siRNA screening showed that CDK4, an activator of E2F, is required for estrogen-independent cell growth. Long-term estrogen-deprived cells hyperactivate phosphatidylinositol 3-kinase (PI3K) independently of ER/E2F. Fulvestrant combined with the pan-PI3K inhibitor BKM120 induced regression of ER+ xenografts. These data support further development of ER downregulators and CDK4 inhibitors, and their combination with PI3K inhibitors for treatment of antiestrogen-resistant breast cancers. Significance: ERα retains genomic activity and drives a CDK4/E2F-dependent transcriptional program despite estrogen deprivation therapy. Combined inhibition of ER and PI3K induced regression of ER+ xenografts, supporting further development of strong ER downregulators and CDK4 inhibitors, and their combination with PI3K inhibitors for the treatment of antiestrogen-resistant breast cancers. Cancer Discovery; 1(4); 338–51. ©2011 AACR. Read the Commentary on this article by Van Tine et al., p. 287 This article is highlighted in the In This Issue feature, p. 275
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-11-0101
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 9
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    Abstract PR05: P-REX1 creates a positive feedback loop to activate growth factor receptor/PI3K signaling
    American Association for Cancer Research (AACR) ; 2013
    In:  Molecular Cancer Research Vol. 11, No. 10_Supplement ( 2013-10-01), p. PR05-PR05
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 11, No. 10_Supplement ( 2013-10-01), p. PR05-PR05
    Abstract: A mass spectrometry-based proteomic screen in ER+ breast cancer cells revealed that levels of P-REX1 are decreased upon loss of PTEN, and increased upon inhibition of PI3K. P-REX1 is a cytoplasmic protein that integrates signaling inputs from receptor tyrosine kinases (RTKs)/PI3K (via the PI3K phospholipid product PIP3) and G protein-coupled receptors (via Gβγ subunits) to drive guanine exchange factor (GEF) activity on Rac1, promoting cytoskeletal remodeling and cell migration. RNAi-mediated knockdown of PREX1 and overexpression of exogenous PREX1 in ER+ breast cancer cells, respectively, decreased and increased activation of insulin-like growth factor receptor-1 (IGF-1R)/insulin receptor (InsR), PI3K/AKT/SGK3, and MEK/Erk under steady-state and growth factor (IGF-1, Heregulin)-stimulated conditions. While the P-REX1 homologue P-REX2a was previously shown to inhibit PTEN phosphatase activity to activate the PI3K/AKT pathway, we did not detect an effect of P-REX1 on PTEN activity. PREX1 knockdown suppressed PI3K/AKT signaling in PTEN-null breast cancer cells; therefore, P-REX1 and P-REX2a may not be functionally redundant. Inhibition of signaling nodes downstream of PI3K (AKT, mTOR) derepresses feedback to activate RTKs and PI3K; knockdown of PREX1 abrogated the PI3K activation induced by inhibition of mTORC1/mTORC2. Structural analysis of P-REX1 revealed that the DH domain (which binds Gβγ and is required for GEF activity) is dispensable for P-REX1 effects on PI3K signaling, while the PH domain [which binds PIP3 and PI(3,4)P2] is required. These data place P-REX1 in a positive feedback loop, whereby PI3K generates PIP3 and PI(3,4)P2, P-REX1 binds these phospholipids at the plasma membrane, P-REX1 promotes RTK activation, and RTKs activate PI3K/AKT and MEK/Erk signaling. Gene expression profiling of diverse types of solid tumors (n = 2,009) and cancer cell lines (n = 807) revealed that PREX1 mRNA is most abundant in ER+ breast tumors compared to other subtypes. Reverse-phase protein array (RPPA) analysis of lysates from 712 breast tumors revealed that P-REX1 levels are inversely correlated with markers of PI3K/AKT/mTOR pathway activation. Furthermore, P-REX1 levels are higher in ER+ tumors than ER- tumors. In another series of 1,293 carcinomas, PREX1 was amplified or mutated in 6.2% of cases, and in 5% of breast cancers. Finally, we tested whether PREX1 lesions co-exist with other PI3K pathway-activating lesions. Among genes encoding proteins implicated in RTK/PI3K signaling and phosphatidylinositol metabolism, we found a significant enrichment for PREX1 mutation/amplification in 54/79 (68%) genes across 1,523 carcinomas. We tested the effects of 7 PREX1 mutants found in breast tumors on PI3K signaling in vitro. A G344R mutation in the PREX1 PH domain conferred increased affinity for PIP3 and PI(3,4)P2, and increased levels of phospho-AKT. These findings suggest that P-REX1 is an ER+ breast tumor-specific oncogene, and PREX1 mutations increase its oncogenic effects in breast cancer. We propose that neutralizing P-REX1 function is a novel therapeutic approach to selectively abrogate oncogenic signaling in ER+ breast cancers while sparing normal tissues. This abstract is also presented as Poster A060. Citation Format: Lloye M. Dillon, Jennifer R. Bean, Wei Yang, Justin M. Balko, W. Hayes McDonald, David B. Friedman, Ana M. Gonzalez-Angulo, Gordon B. Mills, Carlos L. Arteaga, Todd W. Miller. P-REX1 creates a positive feedback loop to activate growth factor receptor/PI3K signaling. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr PR05.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1557-3125.ADVBC-PR05
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 10
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    Incidence and Outcome of BRCA Mutations in Unselected Patients with Triple Receptor-Negative Breast Cancer
    American Association for Cancer Research (AACR) ; 2011
    In:  Clinical Cancer Research Vol. 17, No. 5 ( 2011-03-01), p. 1082-1089
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 17, No. 5 ( 2011-03-01), p. 1082-1089
    Abstract: Purpose: To investigate the incidence of germline and somatic BRCA1/2 mutations in unselected patients with triple-negative breast cancer (TNBC) and determine the prognostic significance of carrying a mutation. Methods: DNA was obtained from 77 TNBC and normal tissues. BRCA1/2 exons/flanking regions were sequenced from tumor and patients classified as mutant or wild type (WT). Sequencing was repeated from normal tissue to identify germline and somatic mutations. Patient characteristics were compared with chi-square. Survival was estimated by Kaplan–Meier method and compared with log-rank. Cox proportional hazards models were fit to determine the independent association of mutation status with outcome. Results: Median age was 51 years (27–83 years). Fifteen patients (19.5%) had BRCA mutations: 12 (15.6%) in BRCA1 (one somatic), and 3 (3.9%) in BRCA2. Patients with BRCA mutations tended to be younger than WT, (P = 0.005). Grade, histology, and stage were not associated with mutation status. At a median follow-up of 43 months (7–214 months), there were 33 (42.9%) recurrences and 35 (45.5%) deaths. Five-year recurrence-free survival estimates were 51.7% for WT versus 86.2% for patients with mutations, (P = 0.031); and 5-year overall survival estimates were 52.8% for WT versus 73.3% for patients with mutations (P = 0.225). After adjustment, patients with BRCA mutations had a significantly better RFS (HR: 0.19, 95% CI: 0.045–0.79, P = 0.016) compared with WT. Conclusions: In this unselected cohort of TNBC, we found a 19.5% incidence of BRCA mutations. Genetic testing should be discussed with patients with TNBC. Patients with TNBC with BRCA mutations had a significantly lower risk of relapse. Clin Cancer Res; 17(5); 1082–9. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-10-2560
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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