Preferential allelic expression of PIK3CA mutations is frequent in breast cancer and is prognostically significant

AbstractGenomic allelic imbalances of mutations have been widely associated with tumor evolution and treatment response. However, allelic imbalances generated at the transcriptomic level by germline and somatic regulatory variants have been less studied. We found widespread allelic expression imbalance between PIK3CA missense mutant and wild-type alleles in breast cancers, predominantly towards the preferential expression of the mutant allele. Expression imbalance was more frequently due to regulatory variation in cis, although contribution of copy number allelic imbalances at the DNA level showed a greater effect. Preferential expression of one allele due to cis-regulatory variant effects was associated with poor prognosis, particularly identifying a poorer prognosis subgroup in ER+, PR+ and Her2− tumors that expressed the mutant allele at extremely low levels. This knowledge challenges the benefit of treating these patients with PI3Kα inhibitors. Overall, our work raises the clinical importance of PIK3CA mutations by demonstrating that their transcriptional allelic imbalance is prognostic in breast tumor biology and by presenting compelling evidence that allelic expression levels of mutations should be taken into consideration during patient clinical management.

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High EGFR protein expression and exon 9 PIK3CA mutations are independent prognostic factors in triple negative breast cancers

BMC Cancer ◽

10.1186/s12885-015-1977-3 ◽

2015 ◽

Vol 15 (1) ◽

Cited By ~ 8

Author(s):

William Jacot ◽

Caroline Mollevi ◽

Frédéric Fina ◽

Evelyne Lopez-Crapez ◽

Pierre-Marie Martin ◽

...

Keyword(s):

Prognostic Factors ◽

Protein Expression ◽

Triple Negative ◽

Breast Cancers ◽

Pik3ca Mutations ◽

Exon 9

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Breast cancer ER, PR, and HER2 expression variance by germline cancer predisposition genes.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.10526 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 10526-10526

Author(s):

Grace Wei ◽

Marilin Rosa ◽

Maxine Chang ◽

Brian J. Czerniecki ◽

Xia Wang

Keyword(s):

Breast Cancer ◽

Cancer Diagnosis ◽

Breast Cancer Diagnosis ◽

Cancer Predisposition ◽

Tumor Evolution ◽

Breast Cancers ◽

Her2 Expression ◽

Expression Levels ◽

Genetic Test Results ◽

Predisposition Genes

10526 Background: The association between breast cancer characteristics and survival with estrogen receptor (ER) and progesterone receptor (PR) expression has been primarily studied via binomial categories, ER-positive and ER-negative. In order to better characterize germline genetic influences on these markers, we investigated their IHC expression semi-quantitatively in cancer predisposition germline pathogenic variant (PV) carriers of the following genes: BRCA1, BRCA2, PALB2, TP53, PTEN, CDH1, ATM, CHEK2, and Lynch syndrome genes. The HER2 expression was also analyzed. Methods: We conducted a retrospective chart review of patients with germline panel genetic testing for cancer predisposition genes at Moffitt Cancer Center’s GeneHome clinic. Inclusion criteria included 1) women ≥18 years old, 2) breast cancer diagnosis, 3) cancer predisposition germline panel genetic test results, 4) available ER and PR expression levels, and 5) available HER expression and/or amplification status. ER, PR, and HER2 status were compared between PV carriers and non-PV carriers via Mann-Whitney U at p>0.05. Results: A total of 847 cases were reviewed for the study. Among 658 patients with a breast cancer diagnosis and complete ER PR data, 365 cases (55.5%) were non-PV carriers and 293 cases (44.5%) carried a PV in at least one of the genes listed above. Among 635 cases with available HER2 expression/amplification status, 355 (55.9%) cases were non-PV carriers and 288 (45.4%) cases were PV-carriers. When compared with non-PV carrier controls, BRCA1 PV carriers’ breast tumors had significantly lower ER and/or PR expression. Further, BRCA2 and TP53 PV tumors also displayed moderately lower ER expression. Contrarily, CHEK2 tumors displayed higher ER and PR expression compared to controls. Further, BRCA1 and BRCA2 PV carriers were more likely to have HER2- breast cancers. Conclusions: Differences in ER, PR, HER2 expression levels were observed in germline PV carrier breast cancers, signaling differential impacts by germline PVs on the tumor evolution process. It is likely that tumor differences in PV carriers influence responses to therapies, including hormone therapy, anti-HER2 therapy, and subsequent survival.[Table: see text]

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Mapping regulatory variants for the serotonin transporter gene based on allelic expression imbalance

Molecular Psychiatry ◽

10.1038/sj.mp.4001952 ◽

2007 ◽

Vol 12 (5) ◽

pp. 421-422 ◽

Cited By ~ 61

Author(s):

J Martin ◽

J Cleak ◽

S A G Willis-Owen ◽

J Flint ◽

S Shifman

Keyword(s):

Serotonin Transporter ◽

Serotonin Transporter Gene ◽

Allelic Expression ◽

Transporter Gene ◽

Allelic Expression Imbalance ◽

Regulatory Variants

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Mutant Allele Imbalance in Cancer

Annual Review of Cancer Biology ◽

10.1146/annurev-cancerbio-051320-124252 ◽

2020 ◽

Vol 5 (1) ◽

Author(s):

Craig M. Bielski ◽

Barry S. Taylor

Keyword(s):

Cancer Biology ◽

Mutant Allele ◽

Tumor Biology ◽

Cellular Level ◽

Driver Mutations ◽

Annual Review ◽

Publication Date ◽

Cancer Evolution ◽

Allele Imbalance ◽

And Function

The search for somatic mutations that drive the initiation and progression of human tumors has dominated recent cancer research. While much emphasis has been placed on characterizing the prevalence and function of driver mutations, comparatively less is known about their serial genetic evolution. Indeed, study of this phenomenon has largely focused on tumor-suppressor genes recessive at the cellular level or mechanisms of resistance in tumors with mutant oncogenes targeted by therapy. There is, however, a growing appreciation that despite a decades-old presumption of heterozygosity, changes in mutant oncogene zygosity are common and drive dosage and stoichiometry changes that lead to selective growth advantages. Here, we review the recent progress in understanding mutant allele imbalance and its implications for tumor biology, cancer evolution, and response to anticancer therapy. Expected final online publication date for the Annual Review of Cancer Biology, Volume 5 is March 4, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Screen-detected breast cancers have different tumor biology and better prognosis compared to interval breast cancers

European Journal of Cancer ◽

10.1016/s0959-8049(20)30548-7 ◽

2020 ◽

Vol 138 ◽

pp. S9

Author(s):

J.Lopes Cardozo ◽

M. Schmidt ◽

L. van ’t Veer ◽

F. Cardoso ◽

C. Poncet ◽

...

Keyword(s):

Tumor Biology ◽

Breast Cancers

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Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors

Science ◽

10.1126/science.aaw9032 ◽

2019 ◽

Vol 366 (6466) ◽

pp. 714-723 ◽

Cited By ~ 33

Author(s):

Neil Vasan ◽

Pedram Razavi ◽

Jared L. Johnson ◽

Hong Shao ◽

Hardik Shah ◽

...

Keyword(s):

Membrane Lipid ◽

Lipid Binding ◽

Breast Cancers ◽

Pik3ca Mutations ◽

Downstream Signaling ◽

Activating Mutations ◽

Increased Sensitivity ◽

Phosphoinositide 3 Kinase ◽

Tumor Types ◽

In Cis

Activating mutations in PIK3CA are frequent in human breast cancer, and phosphoinositide 3-kinase alpha (PI3Kα) inhibitors have been approved for therapy. To characterize determinants of sensitivity to these agents, we analyzed PIK3CA-mutant cancer genomes and observed the presence of multiple PIK3CA mutations in 12 to 15% of breast cancers and other tumor types, most of which (95%) are double mutations. Double PIK3CA mutations are in cis on the same allele and result in increased PI3K activity, enhanced downstream signaling, increased cell proliferation, and tumor growth. The biochemical mechanisms of dual mutations include increased disruption of p110α binding to the inhibitory subunit p85α, which relieves its catalytic inhibition, and increased p110α membrane lipid binding. Double PIK3CA mutations predict increased sensitivity to PI3Kα inhibitors compared with single-hotspot mutations.

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Use of mutational profiling of metastatic ER+/HER2- breast cancers and the coexistence of KRAS, MET, BRAF, and FGFR3 with PIK3CA mutations.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.11003 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 11003-11003

Author(s):

Debora Fumagalli ◽

Roberto Salgado ◽

Carmen Criscitiello ◽

Lina Pugliano ◽

Ioanna Laios ◽

...

Keyword(s):

Hormonal Treatment ◽

Primary Diagnosis ◽

Outcome Data ◽

Her2 Status ◽

Breast Cancers ◽

Genetic Changes ◽

Pik3ca Mutations ◽

Paired Samples ◽

Adjuvant Hormonal Treatment ◽

High Concordance

11003 Background: ER+/HER2- breast cancers (BCs) constitute the most frequent BC subtype. Their response to endocrine therapy and degree of estrogen dependence are heterogeneous. There is little data available about the genetic changes associated with disease progression in this subtype. This information could facilitate drug development. Methods: A series of 132 ER+/HER2- BC patients diagnosed between 1982 and 2008, with known local-regional (n=10) or distant (n=98) relapse or both (n=24), and available FFPE blocks from their primary (P; n=132) and paired relapse (R; n=49) were identified at a single institution. ER and HER2 status were centrally confirmed. 120 mutations from 11 actionable genes and PTEN protein expression were determined using Fluidigm-based real-time PCR and IHC, respectively. Results: At primary diagnosis, median age was 57 years (27-90); median tumor size 2.5 cm (0.5-11); 75% had positive nodes, 26.5% were pre-menopausal; 80% received adjuvant hormonal treatment. Mutation frequency in P and R samples is presented in the Table. PIK3CA mutations were identified in 44% (58/132) P samples. HRAS, AKT1 and PIK3CA mutations were mutually exclusive. 62.5% (5/8) of KRAS-mutated, 75% (6/8) of MET-mutated, 100% (2/2) of BRAF-mutated and 33.3% (1/3) of FGFR3-mutated P had coexistent PIK3CA mutations. For the 49 evaluated pairs, high concordance for the mutations status was found between P and R. Conclusions: KRAS, BRAF, MET and FGFR3 mutations, found at relatively high frequency in this population of relapsed ER+/HER2- BCs, could represent clinically relevant targets and contribute to mechanisms of recurrence, particularly in PIK3CA-mutated BCs. Mutation profiling of additional paired samples is ongoing and clinical outcome data will be presented. [Table: see text]

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A phase I trial of selective PI3K inhibitor taselisib (tas) plus palbociclib (palb) with and without endocrine therapy incorporating pharmacodynamic (PD) studies in patients (pts) with advanced cancers.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.2573 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 2573-2573

Author(s):

Joline Si Jing Lim ◽

Uzma Saddia Asghar ◽

Nikolaos Diamantis ◽

Sarah Emily Ward ◽

Mona Parmar ◽

...

Keyword(s):

Antitumor Activity ◽

Endocrine Therapy ◽

Platelet Rich Plasma ◽

Standard Of Care ◽

Therapeutic Index ◽

Circulating Tumor Dna ◽

Pi3k Pathway ◽

Pi3k Inhibitor ◽

Breast Cancers ◽

Pik3ca Mutations

2573 Background: The phosphatidylinositol 3-kinase (PI3K) pathway is commonly mutated in cancer. Tas is a selective β-isoform-sparing PI3K inhibitor with improved therapeutic index compared to pan-PI3K inhibitors. Palb is a CDK4/6 inhibitor now standard of care in combination with endocrine therapy (ET) in hormone receptor positive breast cancer. Combination of Tas, Palb and ET is synergistic in preclinical models. Methods: This investigator-initiated study investigated safety and tolerability, pharmacokinetics (PK), PD and antitumor activity of Tas+Palb, with addition of ET in dose expansion. Pts were enrolled in 3+3 dose escalation design. Tas was given continuously or 3-weeks-on, 1-week-off (3/1), Palb was given on 3/1 schedule. PD studies included analyses of platelet-rich plasma (PRP) (n = 20) and paired tumor biopsies (n = 5). Serial circulating tumor DNA was monitored in pts with PIK3CA mutations. Results: 24 pts were treated, 22 with Tas+Palb, 2 with Tas+Palb+fulvestrant(ful); M/F 11/13, median lines prior therapy 4. Treatment was well tolerated with mainly G1-2 toxicities. Most frequent G3 toxicities were neutropenia (5/24), thrombocytopenia (5/24) and rash (5/24), with no G4/5 toxicities. Two pts had dose-limiting toxicities (DLT) at DL2. No DLTs were observed at DL4, although pts experienced delayed neutrophil recovery. PK was linear and comparable with monotherapy. At 125mg Palb, significant decreases in pAKT and pGSK3β in PRP confirmed PI3K target inhibition. Two pts with PI3KCA H1047R mutant breast cancers have ongoing RECIST partial response; 1 pt with PIK3CA E542K colorectal cancer had stable disease for 20 weeks. Conclusions: Tas+Palb is well tolerated with evidence of PD and antitumor activity. Dose expansion including recruitment to triplet Tas+Palb+ful and Tas+Palb+letrozole is ongoing with continuous Tas 2mg QD, and Palb 100mg QD on 3/1 schedule, increasing to 125mg after cycle 1 in absence of myelosuppression. Clinical trial information: NCT02389842. [Table: see text]

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Different Subtypes of Uterine Sarcoma Require a Separate Therapeutic Approach

Women s Health ◽

10.2217/17455057.1.3.375 ◽

2005 ◽

Vol 1 (3) ◽

pp. 375-383

Author(s):

Frederic Amant

Keyword(s):

Tumor Biology ◽

Clinical Importance ◽

Careful Analysis ◽

Uterine Sarcoma ◽

Treatment Modalities ◽

Molecular Characteristics ◽

Uterine Sarcomas ◽

Collective Data ◽

Hormone Sensitive ◽

Insight Into

Uterine sarcomas include a variety of mono- and biphasic malignancies, whereas tumor biology varies from an indolent and hormone-sensitive growth pattern to an aggressive and nonresponsive disease that is inevitably fatal. Insight into these different entities has only been gained after careful analysis of clinical, pathologic and molecular characteristics during the last few years. Furthermore, the rarity of uterine sarcomas has motivated many to collect data from different subtypes and to report on the collective data in order to report on larger numbers. The current overview aims to provide insights of clinical importance into each type of uterine sarcoma, with a special emphasis on treatment modalities.

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