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Apostolia Maria Tsimberidou - One of the best experts on this subject based on the ideXlab platform.

  • pik3ca mutation h1047r is associated with response to pi3k akt mtor signaling pathway inhibitors in early phase clinical trials
    Cancer Research, 2013
    Co-Authors: Filip Janku, Jennifer J Wheler, Aung Naing, Gerald S Falchook, David S Hong, Vanda M Stepanek, Siqing Fu, Sarina Anne Pihapaul, Rajyalakshmi Luthra, Apostolia Maria Tsimberidou
    Abstract:

    PIK3CA mutations may predict response to PI3K/AKT/mTOR inhibitors in patients with advanced cancers, but the relevance of mutation subtype has not been investigated. Patients with diverse cancers referred to the Clinical Center for Targeted Therapy were analyzed for PIK3CA and, if possible, KRAS mutations. Patients with PIK3CA mutations were treated, whenever possible, with agents targeting the PI3K/AKT/mTOR pathway. Overall, 105 (10%) of 1,012 patients tested harbored PIK3CA mutations. Sixty-six (median 3 prior therapies) of the 105 PIK3CA -mutant patients, including 16 individuals (of 55 PIK3CA- mutant patients tested) with simultaneous KRAS mutations, were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor; 17% (11/66) achieved a partial response (PR). Patients with a PIK3CA H1047R mutation compared with patients who had other PIK3CA mutations or patients with wild-type PIK3CA treated on the same protocols had a higher PR rate (6/16, 38% vs. 5/50; 10% vs. 23/174, 13%, respectively; all P ≤ 0.02). None of the 16 patients with coexisting PIK3CA and KRAS mutations in codon 12 or 13 attained a PR (0/16, 0%). Patients treated with combination therapy versus single-agent therapies had a higher PR rate (11/38, 29% vs. 0/28, 0%; P = 0.002). Multivariate analysis showed that H1047R was the only independent factor predicting response [OR 6.6, 95% confidence interval (CI), 1.02–43.0, P = 0.047). Our data suggest that interaction between PIK3CA mutation H1047R versus other aberrations and response to PI3K/AKT/mTOR axis inhibitors warrants further exploration. Cancer Res; 73(1); 276–84. ©2012 AACR .

  • pik3ca mutation h1047r is associated with response to pi3k akt mtor signaling pathway inhibitors in early phase clinical trials
    Cancer Research, 2013
    Co-Authors: Filip Janku, Jennifer J Wheler, Aung Naing, Gerald S Falchook, David S Hong, Vanda M Stepanek, Sarina Anne Pihapaul, Rajyalakshmi Luthra, Jack J Lee, Apostolia Maria Tsimberidou
    Abstract:

    PIK3CA mutations may predict response to PI3K/AKT/mTOR inhibitors in patients with advanced cancers, but the relevance of mutation subtype has not been investigated. Patients with diverse cancers referred to the Clinical Center for Targeted Therapy were analyzed for PIK3CA and, if possible, KRAS mutations. Patients with PIK3CA mutations were treated, whenever possible, with agents targeting the PI3K/AKT/mTOR pathway. Overall, 105 (10%) of 1,012 patients tested harbored PIK3CA mutations. Sixty-six (median 3 prior therapies) of the 105 PIK3CA-mutant patients, including 16 individuals (of 55 PIK3CA-mutant patients tested) with simultaneous KRAS mutations, were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor; 17% (11/66) achieved a partial response (PR). Patients with a PIK3CA H1047R mutation compared with patients who had other PIK3CA mutations or patients with wild-type PIK3CA treated on the same protocols had a higher PR rate (6/16, 38% vs. 5/50; 10% vs. 23/174, 13%, respectively; all P ≤ 0.02). None of the 16 patients with coexisting PIK3CA and KRAS mutations in codon 12 or 13 attained a PR (0/16, 0%). Patients treated with combination therapy versus single-agent therapies had a higher PR rate (11/38, 29% vs. 0/28, 0%; P = 0.002). Multivariate analysis showed that H1047R was the only independent factor predicting response [OR 6.6, 95% confidence interval (CI), 1.02-43.0, P = 0.047). Our data suggest that interaction between PIK3CA mutation H1047R versus other aberrations and response to PI3K/AKT/mTOR axis inhibitors warrants further exploration.

Filip Janku - One of the best experts on this subject based on the ideXlab platform.

  • abstract pd5 5 phase i study of the pi3kα inhibitor byl719 plus fulvestrant in patients withpik3ca altered and wild type er her2 locally advanced or metastatic breast cancer
    Cancer Research, 2015
    Co-Authors: Filip Janku, Howard A Burris, Dejan Juric, Javier Cortes, Hope S Rugo, Martin Schuler, Barbara Deschlerbaier, Mark R Middleton, M Gilmartin, Jordan Berlin
    Abstract:

    Background: BYL719 selectively inhibits the α-isoform of Class I PI3K. PI3Kα is encoded by PIK3CA, a frequently altered gene in human cancers. Preclinical data indicate BYL719 may be more effective in patients (pts) with PIK3CA-altered tumors; however there are data to suggest that PIK3CA-wild-type (wt) tumors may also be sensitive to BYL719. Here, we present updated data from the Phase I study of BYL719 + fulvestrant in pts with PIK3CA-altered or -wt ER+/HER2– locally advanced/metastatic breast cancer (BC) (NCT01219699). Methods: Adult women with PIK3CA-altered (mutation or amplification) ER+/HER2– BC received continuous oral BYL719 (300–400 mg/day; 28-day cycles) + fixed-dose fulvestrant (500 mg every 4 weeks, plus an additional dose 2 weeks after first dose) during dose escalation and expansion. Pts with PIK3CA-wt ER+/HER2– BC were enrolled into the dose expansion to receive BYL719 400 mg/day + fulvestrant. A Bayesian logistic regression model with overdose control guided dose escalation. Primary objective: to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of BYL719 in combination with fulvestrant, which was declared previously as 400 mg/day. An expansion cohort at the MTD assessed safety (CTCAE v4.0), tolerability, pharmacokinetics (PK), and preliminary efficacy (RECIST v1.0). Results: As of May 2, 2014, 64 pts (PIK3CA-altered n=41; PIK3CA-wt n=16; PIK3CA status unknown/pending n=7) received BYL719 300–400 mg/day + fulvestrant. Median number of prior antineoplastic therapies: 5 (range: 1–12) for pts with PIK3CA-altered tumors and 5 (range: 4–16) for pts with PIK3CA-wt tumors. Prior fulvestrant treatment: 19 (46%) and 7 (44%) pts with PIK3CA-altered and -wt tumors, respectively. Overall, the most common (≥25%) adverse events (AEs; all grades/all doses) suspected to be study drug-related were hyperglycemia (41%), diarrhea (34%), nausea (30%), and vomiting (25%). The most common (>10%) study drug-related Grade 3/4 AEs (all doses) were maculopapular rash (14%) and hyperglycemia (13%). Preliminary antitumor activity was observed in this trial. At data cut-off, partial responses (PRs) were observed in 2 patients with PIK3CA-altered tumors evaluable for response (2/33, 6%), but no PRs were observed in the 15 evaluable patients with PIK3CA-wt tumors. Duration of exposure was >16 weeks in 24 (59%) patients with PIK3CA-altered tumors and in 5 (31%) patients with PIK3CA-wt tumors. PK and exposure of BYL719 + fulvestrant was similar to that observed with single-agent BYL719 at the same dose levels. At data cut-off, treatment was ongoing in 20 (49%) and 2 (13%) pts with PIK3CA-altered and -wt tumors, respectively. Conclusions: BYL719 + fulvestrant demonstrated a favorable safety profile in pts with PIK3CA-altered and -wt ER+/HER2– BC, with mostly on-target effects (i.e. hyperglycemia, rash). Preliminary clinical activity was seen in pts with PIK3CA-altered and -wt tumors, but confirmed PRs were only observed in pts with PIK3CA-altered tumors. The low number of pts with PIK3CA-wt tumors limits further conclusion. Citation Format: Filip Janku, Dejan Juric, Javier Cortes, Hope Rugo, Howard A Burris, Martin Schuler, Barbara Deschler-Baier, Mark R Middleton, Marta Gil-Martin, Jordan Berlin, Eric Winer, Douglas Bootle, Lars Blumenstein, David Demanse, Christina Coughlin, Cornelia Quadt, Jose Baselga. Phase I study of the PI3Kα inhibitor BYL719 plus fulvestrant in patients with PIK3CA-altered and wild type ER+/HER2- locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD5-5.

  • pik3ca mutation h1047r is associated with response to pi3k akt mtor signaling pathway inhibitors in early phase clinical trials
    Cancer Research, 2013
    Co-Authors: Filip Janku, Jennifer J Wheler, Aung Naing, Gerald S Falchook, David S Hong, Vanda M Stepanek, Siqing Fu, Sarina Anne Pihapaul, Rajyalakshmi Luthra, Apostolia Maria Tsimberidou
    Abstract:

    PIK3CA mutations may predict response to PI3K/AKT/mTOR inhibitors in patients with advanced cancers, but the relevance of mutation subtype has not been investigated. Patients with diverse cancers referred to the Clinical Center for Targeted Therapy were analyzed for PIK3CA and, if possible, KRAS mutations. Patients with PIK3CA mutations were treated, whenever possible, with agents targeting the PI3K/AKT/mTOR pathway. Overall, 105 (10%) of 1,012 patients tested harbored PIK3CA mutations. Sixty-six (median 3 prior therapies) of the 105 PIK3CA -mutant patients, including 16 individuals (of 55 PIK3CA- mutant patients tested) with simultaneous KRAS mutations, were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor; 17% (11/66) achieved a partial response (PR). Patients with a PIK3CA H1047R mutation compared with patients who had other PIK3CA mutations or patients with wild-type PIK3CA treated on the same protocols had a higher PR rate (6/16, 38% vs. 5/50; 10% vs. 23/174, 13%, respectively; all P ≤ 0.02). None of the 16 patients with coexisting PIK3CA and KRAS mutations in codon 12 or 13 attained a PR (0/16, 0%). Patients treated with combination therapy versus single-agent therapies had a higher PR rate (11/38, 29% vs. 0/28, 0%; P = 0.002). Multivariate analysis showed that H1047R was the only independent factor predicting response [OR 6.6, 95% confidence interval (CI), 1.02–43.0, P = 0.047). Our data suggest that interaction between PIK3CA mutation H1047R versus other aberrations and response to PI3K/AKT/mTOR axis inhibitors warrants further exploration. Cancer Res; 73(1); 276–84. ©2012 AACR .

  • pik3ca mutation h1047r is associated with response to pi3k akt mtor signaling pathway inhibitors in early phase clinical trials
    Cancer Research, 2013
    Co-Authors: Filip Janku, Jennifer J Wheler, Aung Naing, Gerald S Falchook, David S Hong, Vanda M Stepanek, Sarina Anne Pihapaul, Rajyalakshmi Luthra, Jack J Lee, Apostolia Maria Tsimberidou
    Abstract:

    PIK3CA mutations may predict response to PI3K/AKT/mTOR inhibitors in patients with advanced cancers, but the relevance of mutation subtype has not been investigated. Patients with diverse cancers referred to the Clinical Center for Targeted Therapy were analyzed for PIK3CA and, if possible, KRAS mutations. Patients with PIK3CA mutations were treated, whenever possible, with agents targeting the PI3K/AKT/mTOR pathway. Overall, 105 (10%) of 1,012 patients tested harbored PIK3CA mutations. Sixty-six (median 3 prior therapies) of the 105 PIK3CA-mutant patients, including 16 individuals (of 55 PIK3CA-mutant patients tested) with simultaneous KRAS mutations, were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor; 17% (11/66) achieved a partial response (PR). Patients with a PIK3CA H1047R mutation compared with patients who had other PIK3CA mutations or patients with wild-type PIK3CA treated on the same protocols had a higher PR rate (6/16, 38% vs. 5/50; 10% vs. 23/174, 13%, respectively; all P ≤ 0.02). None of the 16 patients with coexisting PIK3CA and KRAS mutations in codon 12 or 13 attained a PR (0/16, 0%). Patients treated with combination therapy versus single-agent therapies had a higher PR rate (11/38, 29% vs. 0/28, 0%; P = 0.002). Multivariate analysis showed that H1047R was the only independent factor predicting response [OR 6.6, 95% confidence interval (CI), 1.02-43.0, P = 0.047). Our data suggest that interaction between PIK3CA mutation H1047R versus other aberrations and response to PI3K/AKT/mTOR axis inhibitors warrants further exploration.

Carlos H Barrios - One of the best experts on this subject based on the ideXlab platform.

  • pik3ca alterations and benefit with neratinib analysis from the randomized double blind placebo controlled phase iii extenet trial
    Breast Cancer Research, 2019
    Co-Authors: Stephen Chia, Beverly Moy, Gunter Von Minckwitz, Miguel Martin, Frankie A Holmes, Bent Ejlertsen, Suzette Delaloge, Hiroji Iwata, Janine Mansi, Carlos H Barrios
    Abstract:

    Neratinib is an irreversible pan-HER tyrosine kinase inhibitor that inhibits PI3K/Akt and MAPK signaling pathways after HER2 receptor activation. The ExteNET study showed that neratinib significantly improved 5-year invasive disease-free survival (iDFS) in women who completed trastuzumab-based adjuvant therapy for early breast cancer (EBC). We assessed the prognostic and predictive significance of PIK3CA alterations in patients in ExteNET. Participants were women aged ≥ 18 years (≥ 20 years in Japan) with stage 1–3c (modified to stage 2–3c in February 2010) operable breast cancer, who had completed (neo)adjuvant chemotherapy plus trastuzumab ≤ 2 years before randomization, with no evidence of disease recurrence or metastatic disease at study entry. Patients were randomized to oral neratinib 240 mg/day or placebo for 1 year. Formalin-fixed, paraffin-embedded primary tumor specimens underwent polymerase chain reaction (PCR) PIK3CA testing for two hotspot mutations in exon 9, one hot-spot mutation in exon 20, and fluorescence in situ hybridization (FISH) analysis for PIK3CA amplification. The primary endpoint (iDFS) was tested with log-rank test and hazard ratios (HRs) estimated using Cox proportional-hazards models. Among the intent-to-treat population (n = 2840), tumor specimens were available for PCR testing (991 patients) and PIK3CA FISH (702 patients). Overall, 262 samples were PIK3CA altered: 201 were mutated (77%), 52 (20%) were amplified, and 9 (3%) were mutated and amplified. iDFS was non-significantly worse in placebo-treated patients with altered vs wild-type PIK3CA (HR 1.34; 95% CI 0.72–2.50; P = 0.357). Neratinib’s effect over placebo was significant in patients with PIK3CA-altered tumors (HR 0.41; 95% CI 0.17–0.90, P = 0.028) but not PIK3CA wild-type tumors (HR 0.72; 95% CI 0.36–1.41; P = 0.34). The interaction test was non-significant (P = 0.309). Although there was a greater absolute risk reduction associated with neratinib treatment of patients with PIK3CA-altered tumors in ExteNET, current data do not support PIK3CA alteration as a predictive biomarker of response to neratinib in HER2-positive EBC. ClinicalTrials.gov , NCT00878709 . Trial registered April 9, 2009.

  • PIK3CA alterations and benefit with neratinib: analysis from the randomized, double-blind, placebo-controlled, phase III ExteNET trial
    BMC, 2019
    Co-Authors: Stephen K. L. Chia, Beverly Moy, Gunter Von Minckwitz, Miguel Martin, Frankie A Holmes, Bent Ejlertsen, Suzette Delaloge, Hiroji Iwata, Janine Mansi, Carlos H Barrios
    Abstract:

    Abstract Background Neratinib is an irreversible pan-HER tyrosine kinase inhibitor that inhibits PI3K/Akt and MAPK signaling pathways after HER2 receptor activation. The ExteNET study showed that neratinib significantly improved 5-year invasive disease-free survival (iDFS) in women who completed trastuzumab-based adjuvant therapy for early breast cancer (EBC). We assessed the prognostic and predictive significance of PIK3CA alterations in patients in ExteNET. Methods Participants were women aged ≥ 18 years (≥ 20 years in Japan) with stage 1–3c (modified to stage 2–3c in February 2010) operable breast cancer, who had completed (neo)adjuvant chemotherapy plus trastuzumab ≤ 2 years before randomization, with no evidence of disease recurrence or metastatic disease at study entry. Patients were randomized to oral neratinib 240 mg/day or placebo for 1 year. Formalin-fixed, paraffin-embedded primary tumor specimens underwent polymerase chain reaction (PCR) PIK3CA testing for two hotspot mutations in exon 9, one hot-spot mutation in exon 20, and fluorescence in situ hybridization (FISH) analysis for PIK3CA amplification. The primary endpoint (iDFS) was tested with log-rank test and hazard ratios (HRs) estimated using Cox proportional-hazards models. Results Among the intent-to-treat population (n = 2840), tumor specimens were available for PCR testing (991 patients) and PIK3CA FISH (702 patients). Overall, 262 samples were PIK3CA altered: 201 were mutated (77%), 52 (20%) were amplified, and 9 (3%) were mutated and amplified. iDFS was non-significantly worse in placebo-treated patients with altered vs wild-type PIK3CA (HR 1.34; 95% CI 0.72–2.50; P = 0.357). Neratinib’s effect over placebo was significant in patients with PIK3CA-altered tumors (HR 0.41; 95% CI 0.17–0.90, P = 0.028) but not PIK3CA wild-type tumors (HR 0.72; 95% CI 0.36–1.41; P = 0.34). The interaction test was non-significant (P = 0.309). Conclusions Although there was a greater absolute risk reduction associated with neratinib treatment of patients with PIK3CA-altered tumors in ExteNET, current data do not support PIK3CA alteration as a predictive biomarker of response to neratinib in HER2-positive EBC. Trial registration ClinicalTrials.gov, NCT00878709. Trial registered April 9, 2009

Beverly Moy - One of the best experts on this subject based on the ideXlab platform.

  • pik3ca alterations and benefit with neratinib analysis from the randomized double blind placebo controlled phase iii extenet trial
    Breast Cancer Research, 2019
    Co-Authors: Stephen Chia, Beverly Moy, Gunter Von Minckwitz, Miguel Martin, Frankie A Holmes, Bent Ejlertsen, Suzette Delaloge, Hiroji Iwata, Janine Mansi, Carlos H Barrios
    Abstract:

    Neratinib is an irreversible pan-HER tyrosine kinase inhibitor that inhibits PI3K/Akt and MAPK signaling pathways after HER2 receptor activation. The ExteNET study showed that neratinib significantly improved 5-year invasive disease-free survival (iDFS) in women who completed trastuzumab-based adjuvant therapy for early breast cancer (EBC). We assessed the prognostic and predictive significance of PIK3CA alterations in patients in ExteNET. Participants were women aged ≥ 18 years (≥ 20 years in Japan) with stage 1–3c (modified to stage 2–3c in February 2010) operable breast cancer, who had completed (neo)adjuvant chemotherapy plus trastuzumab ≤ 2 years before randomization, with no evidence of disease recurrence or metastatic disease at study entry. Patients were randomized to oral neratinib 240 mg/day or placebo for 1 year. Formalin-fixed, paraffin-embedded primary tumor specimens underwent polymerase chain reaction (PCR) PIK3CA testing for two hotspot mutations in exon 9, one hot-spot mutation in exon 20, and fluorescence in situ hybridization (FISH) analysis for PIK3CA amplification. The primary endpoint (iDFS) was tested with log-rank test and hazard ratios (HRs) estimated using Cox proportional-hazards models. Among the intent-to-treat population (n = 2840), tumor specimens were available for PCR testing (991 patients) and PIK3CA FISH (702 patients). Overall, 262 samples were PIK3CA altered: 201 were mutated (77%), 52 (20%) were amplified, and 9 (3%) were mutated and amplified. iDFS was non-significantly worse in placebo-treated patients with altered vs wild-type PIK3CA (HR 1.34; 95% CI 0.72–2.50; P = 0.357). Neratinib’s effect over placebo was significant in patients with PIK3CA-altered tumors (HR 0.41; 95% CI 0.17–0.90, P = 0.028) but not PIK3CA wild-type tumors (HR 0.72; 95% CI 0.36–1.41; P = 0.34). The interaction test was non-significant (P = 0.309). Although there was a greater absolute risk reduction associated with neratinib treatment of patients with PIK3CA-altered tumors in ExteNET, current data do not support PIK3CA alteration as a predictive biomarker of response to neratinib in HER2-positive EBC. ClinicalTrials.gov , NCT00878709 . Trial registered April 9, 2009.

  • PIK3CA alterations and benefit with neratinib: analysis from the randomized, double-blind, placebo-controlled, phase III ExteNET trial
    BMC, 2019
    Co-Authors: Stephen K. L. Chia, Beverly Moy, Gunter Von Minckwitz, Miguel Martin, Frankie A Holmes, Bent Ejlertsen, Suzette Delaloge, Hiroji Iwata, Janine Mansi, Carlos H Barrios
    Abstract:

    Abstract Background Neratinib is an irreversible pan-HER tyrosine kinase inhibitor that inhibits PI3K/Akt and MAPK signaling pathways after HER2 receptor activation. The ExteNET study showed that neratinib significantly improved 5-year invasive disease-free survival (iDFS) in women who completed trastuzumab-based adjuvant therapy for early breast cancer (EBC). We assessed the prognostic and predictive significance of PIK3CA alterations in patients in ExteNET. Methods Participants were women aged ≥ 18 years (≥ 20 years in Japan) with stage 1–3c (modified to stage 2–3c in February 2010) operable breast cancer, who had completed (neo)adjuvant chemotherapy plus trastuzumab ≤ 2 years before randomization, with no evidence of disease recurrence or metastatic disease at study entry. Patients were randomized to oral neratinib 240 mg/day or placebo for 1 year. Formalin-fixed, paraffin-embedded primary tumor specimens underwent polymerase chain reaction (PCR) PIK3CA testing for two hotspot mutations in exon 9, one hot-spot mutation in exon 20, and fluorescence in situ hybridization (FISH) analysis for PIK3CA amplification. The primary endpoint (iDFS) was tested with log-rank test and hazard ratios (HRs) estimated using Cox proportional-hazards models. Results Among the intent-to-treat population (n = 2840), tumor specimens were available for PCR testing (991 patients) and PIK3CA FISH (702 patients). Overall, 262 samples were PIK3CA altered: 201 were mutated (77%), 52 (20%) were amplified, and 9 (3%) were mutated and amplified. iDFS was non-significantly worse in placebo-treated patients with altered vs wild-type PIK3CA (HR 1.34; 95% CI 0.72–2.50; P = 0.357). Neratinib’s effect over placebo was significant in patients with PIK3CA-altered tumors (HR 0.41; 95% CI 0.17–0.90, P = 0.028) but not PIK3CA wild-type tumors (HR 0.72; 95% CI 0.36–1.41; P = 0.34). The interaction test was non-significant (P = 0.309). Conclusions Although there was a greater absolute risk reduction associated with neratinib treatment of patients with PIK3CA-altered tumors in ExteNET, current data do not support PIK3CA alteration as a predictive biomarker of response to neratinib in HER2-positive EBC. Trial registration ClinicalTrials.gov, NCT00878709. Trial registered April 9, 2009

  • abstract p1 13 03 association of pik3ca mutation with clinical response to specific endocrine therapies in metastatic hormone receptor positive hr breast cancer
    Cancer Research, 2015
    Co-Authors: Douglas S Micalizzi, Dejan Juric, Andrzej Niemierko, Kerry L Reynolds, Darrell R Borger, Sadhna Vora, Steven J Isakoff, Beverly Moy, Leif W Ellisen, Aditya Bardia
    Abstract:

    Background: Phosphatidylinositol 3-kinase (PI3K) gene (PIK3CA) mutations are the most common somatic mutations in breast cancer. Preclinical models suggest that activating mutations in PIK3CA may mediate resistance to endocrine therapy in breast cancer, and multiple clinical trials testing combinations of endocrine therapy with PI3K inhibitors are ongoing. However, the role of PIK3CA in modulating the clinical response to endocrine therapies is less clear, with some studies suggesting that PIK3CA mutations are associated with improved prognosis in HR+ breast cancer. The primary objective of this study was to evaluate the association of PIK3CA mutation with clinical response to endocrine therapies in metastatic HR+ breast cancer. Methods: We identified patients with metastatic HR+ /HER2 negative breast cancer, including ER+/PR+ (estrogen receptor/progesterone receptor) and ER+/PR-, to determine the time to progression (TTP) on first-line endocrine therapy for metastatic disease. PIK3CA mutations, including 8 common hotspot mutations, were assessed by a robust, high-throughput tumor genotyping assay (Snapshot), developed at our institution, using DNA derived from formalin-fixed, paraffin-embedded (FFPE) tissue. Actuarial analysis of TTP was performed using Cox proportional hazard method to compute Hazard Ratio (HR) and 95% Confidence Intervals (CI). Results: Between 2009 and 2012, we identified 188 patients with HR+ metastatic breast cancer who had tumor genotyping performed. PIK3CA mutations were identified in 32.2% of tumors, including mutations in both helical (exon 9) and kinase (exon 20) domains (60% and 40%, respectively). The PIK3CA mutant and wild type patients had a similar median age at diagnosis of metastatic disease (55.8 and 56.7 years; p=0.2), ER+/PR+ tumors (75.0% vs 76.4%; p=0.8), and median TTP (8.2 versus 11.4 months; p=0.6). After adjusting for age at diagnosis and ER+/PR+ versus ER+/PR-, the TTP on first-line endocrine therapy did not vary among patients with PIK3CA mutations versus wild type (HR: 0.94; 95% CI:0.62-1.43; p=0.8), but did vary by type of endocrine therapy. Patients with PIK3CA mutations, as compared to wild type patients, had shorter TTP with fulvestrant (HR: 3.6; 95% CI:1.2-11.0; p=0.03), but not with aromatase inhibitors (AIs) (HR: 0.70; 95% CI:0.44-1.1; p=0.1), suggesting that mutant PIK3CA may specifically modulate the response to fulvestrant therapy. We did not observe any difference in TTP for exon 9 versus 20 PIK3CA mutations, though numbers were small resulting in limited statistical power. Conclusion: Among patients with metastatic HR+ breast cancer in this study, PIK3CA mutations are associated with decreased time to progression with fulvestrant, but not with AIs, suggesting that the these mutations may mediate resistance to specific endocrine therapies. Further studies are needed to confirm these findings and provide mechanistic insights to help guide optimal selection of endocrine therapy and combination with PI3K directed therapy in metastatic HR+ breast cancer. Citation Format: Douglas S Micalizzi, Dejan Juric, Andrzej Niemierko, Kerry L Reynolds, Darrell Borger, Sadhna R Vora, Steven J Isakoff, Beverly Moy, Leif W Ellisen, Aditya Bardia. Association of PIK3CA mutation with clinical response to specific endocrine therapies in metastatic hormone receptor positive (HR+) breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-13-03.

Gunter Von Minckwitz - One of the best experts on this subject based on the ideXlab platform.

  • pik3ca alterations and benefit with neratinib analysis from the randomized double blind placebo controlled phase iii extenet trial
    Breast Cancer Research, 2019
    Co-Authors: Stephen Chia, Beverly Moy, Gunter Von Minckwitz, Miguel Martin, Frankie A Holmes, Bent Ejlertsen, Suzette Delaloge, Hiroji Iwata, Janine Mansi, Carlos H Barrios
    Abstract:

    Neratinib is an irreversible pan-HER tyrosine kinase inhibitor that inhibits PI3K/Akt and MAPK signaling pathways after HER2 receptor activation. The ExteNET study showed that neratinib significantly improved 5-year invasive disease-free survival (iDFS) in women who completed trastuzumab-based adjuvant therapy for early breast cancer (EBC). We assessed the prognostic and predictive significance of PIK3CA alterations in patients in ExteNET. Participants were women aged ≥ 18 years (≥ 20 years in Japan) with stage 1–3c (modified to stage 2–3c in February 2010) operable breast cancer, who had completed (neo)adjuvant chemotherapy plus trastuzumab ≤ 2 years before randomization, with no evidence of disease recurrence or metastatic disease at study entry. Patients were randomized to oral neratinib 240 mg/day or placebo for 1 year. Formalin-fixed, paraffin-embedded primary tumor specimens underwent polymerase chain reaction (PCR) PIK3CA testing for two hotspot mutations in exon 9, one hot-spot mutation in exon 20, and fluorescence in situ hybridization (FISH) analysis for PIK3CA amplification. The primary endpoint (iDFS) was tested with log-rank test and hazard ratios (HRs) estimated using Cox proportional-hazards models. Among the intent-to-treat population (n = 2840), tumor specimens were available for PCR testing (991 patients) and PIK3CA FISH (702 patients). Overall, 262 samples were PIK3CA altered: 201 were mutated (77%), 52 (20%) were amplified, and 9 (3%) were mutated and amplified. iDFS was non-significantly worse in placebo-treated patients with altered vs wild-type PIK3CA (HR 1.34; 95% CI 0.72–2.50; P = 0.357). Neratinib’s effect over placebo was significant in patients with PIK3CA-altered tumors (HR 0.41; 95% CI 0.17–0.90, P = 0.028) but not PIK3CA wild-type tumors (HR 0.72; 95% CI 0.36–1.41; P = 0.34). The interaction test was non-significant (P = 0.309). Although there was a greater absolute risk reduction associated with neratinib treatment of patients with PIK3CA-altered tumors in ExteNET, current data do not support PIK3CA alteration as a predictive biomarker of response to neratinib in HER2-positive EBC. ClinicalTrials.gov , NCT00878709 . Trial registered April 9, 2009.

  • PIK3CA alterations and benefit with neratinib: analysis from the randomized, double-blind, placebo-controlled, phase III ExteNET trial
    BMC, 2019
    Co-Authors: Stephen K. L. Chia, Beverly Moy, Gunter Von Minckwitz, Miguel Martin, Frankie A Holmes, Bent Ejlertsen, Suzette Delaloge, Hiroji Iwata, Janine Mansi, Carlos H Barrios
    Abstract:

    Abstract Background Neratinib is an irreversible pan-HER tyrosine kinase inhibitor that inhibits PI3K/Akt and MAPK signaling pathways after HER2 receptor activation. The ExteNET study showed that neratinib significantly improved 5-year invasive disease-free survival (iDFS) in women who completed trastuzumab-based adjuvant therapy for early breast cancer (EBC). We assessed the prognostic and predictive significance of PIK3CA alterations in patients in ExteNET. Methods Participants were women aged ≥ 18 years (≥ 20 years in Japan) with stage 1–3c (modified to stage 2–3c in February 2010) operable breast cancer, who had completed (neo)adjuvant chemotherapy plus trastuzumab ≤ 2 years before randomization, with no evidence of disease recurrence or metastatic disease at study entry. Patients were randomized to oral neratinib 240 mg/day or placebo for 1 year. Formalin-fixed, paraffin-embedded primary tumor specimens underwent polymerase chain reaction (PCR) PIK3CA testing for two hotspot mutations in exon 9, one hot-spot mutation in exon 20, and fluorescence in situ hybridization (FISH) analysis for PIK3CA amplification. The primary endpoint (iDFS) was tested with log-rank test and hazard ratios (HRs) estimated using Cox proportional-hazards models. Results Among the intent-to-treat population (n = 2840), tumor specimens were available for PCR testing (991 patients) and PIK3CA FISH (702 patients). Overall, 262 samples were PIK3CA altered: 201 were mutated (77%), 52 (20%) were amplified, and 9 (3%) were mutated and amplified. iDFS was non-significantly worse in placebo-treated patients with altered vs wild-type PIK3CA (HR 1.34; 95% CI 0.72–2.50; P = 0.357). Neratinib’s effect over placebo was significant in patients with PIK3CA-altered tumors (HR 0.41; 95% CI 0.17–0.90, P = 0.028) but not PIK3CA wild-type tumors (HR 0.72; 95% CI 0.36–1.41; P = 0.34). The interaction test was non-significant (P = 0.309). Conclusions Although there was a greater absolute risk reduction associated with neratinib treatment of patients with PIK3CA-altered tumors in ExteNET, current data do not support PIK3CA alteration as a predictive biomarker of response to neratinib in HER2-positive EBC. Trial registration ClinicalTrials.gov, NCT00878709. Trial registered April 9, 2009

  • pik3ca mutations are associated with lower rates of pathologic complete response to anti human epidermal growth factor receptor 2 her2 therapy in primary her2 overexpressing breast cancer
    Journal of Clinical Oncology, 2014
    Co-Authors: Sibylle Loibl, Gunter Von Minckwitz, Andreas Schneeweiss, S Paepke, Annika Lehmann, M Rezai, Dirk Dm Zahm, Peter Sinn, F Khandan, Holger Eidtmann
    Abstract:

    Purpose Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in breast cancer, with mutations in PIK3CA being the most common. This study investigated the association between PIK3CA genotype and pathologic complete response (pCR) rates in human epidermal growth factor receptor 2 (HER2) ‐positive breast cancer treated with either dual or single anti-HER2 treatment in addition to neoadjuvant chemotherapy. Patients and Methods PIK3CA mutations in 504 tumor samples from participants in the neoadjuvant GeparQuattro, GeparQuinto, and GeparSixto studies were evaluated. All HER2-positive patients received either trastuzumab or lapatinib or the combination plus anthracycline-taxane chemotherapy. PIK3CA mutations were evaluated in formalin-fixed, paraffin-embedded tissues from core biopsies with a tumor cell content of 20% by using classical Sanger sequencing of exon 9 and exon 20. Results Overall, 21.4% of the patients harbored a PIK3CA mutation. Detection of a PIK3CA mutation was significantly associated with a lower pCR rate (19.4% with PIK3CA mutation v 32.8% with PIK3CA wild-type; odds ratio [OR], 0.49; 95% CI, 0.29 to 0.83; P .008). In the 291 hormone receptor (HR) ‐positive tumors, pCR rate was 11.3% with a PIK3CA mutation compared with 27.5% with PIK3CA wild-type (OR, 0.34; 95% CI, 0.15 to 0.78; P .011). In 213 patients with HR-negative tumors, pCR rate was 30.4% with PIK3CA mutation and 40.1% without (OR, 0.65; 95% CI, 0.32 to 1.32; P .233; interaction test P .292). In multivariable analysis, HR status and PIK3CA status provided independent predictive information. In patients with PIK3CA mutation, the pCR rates were 16%, 24.3%, and 17.4% with lapatinib, trastuzumab, and the combination, respectively (P .654) and in the wild-type group, they were 18.2%, 33.%, and 37.1%, respectively (P .017). Disease-free survival and overall survival were not statistically significantly different between patients with mutant and wild-type PIK3CA. Conclusion HER2-positive breast carcinomas with a PIK3CA mutation are less likely to achieve a pCR after neoadjuvant anthracycline-taxane‐based chemotherapy plus anti-HER2 treatment, even if a dual anti-HER2 treatment is given. J Clin Oncol 32:3212-3220. © 2014 by American Society of Clinical Oncology