High Frequency of Activating &lt;emph type="ital"&gt;PIK3CA&lt;/emph&gt; Mutations in Human Papillomavirus–Positive Oropharyngeal Cancer&lt;alt-title&gt;&lt;emph type="ital"&gt;PIK3CA&lt;/emph&gt; in HPV+ Oropharyngeal Squamous Cell Carcinoma&lt;/alt-title&gt;

Nichols, Anthony C.; Palma, David A.; Chow, Winsion; Tan, Susan; Rajakumar, Chandrew; Rizzo, Giananthony; Fung, Kevin; Kwan, Keith; Wehrli, Brett; Winquist, Eric; Koropatnick, James; Mymryk, Joe S.; Yoo, John; Barrett, John W.

doi:10.1001/jamaoto.2013.3210

Cited by 73 publications

(37 citation statements)

References 17 publications

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“…For example, 38% of squamous cell carcinomas of the cervix and 25% of adenocarcinomas of the cervix have a PIK3CA mutation,[12] but we found that only 18% of small cell carcinomas had this mutation. Mutations in PIK3CA are also commonly found in other HPV-associated malignancies, such as oropharyngeal cancer (28%)[13] and squamous cell anal cancer (22%). [14]…”

Section: Discussionmentioning

confidence: 99%

Sequencing of mutational hotspots in cancer-related genes in small cell neuroendocrine cervical cancer

Frumovitz

Burzawa

Byers

et al. 2016

Gynecologic Oncology

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Objectives Small cell cervical cancer is a rare malignancy with limited treatment options for recurrent disease. We sought to determine if tumor specimens of small cell cervical cancer harbor common somatic mutations and if any of these are actionable. Methods Using a registry of patients with neuroendocrine cervical cancer, we identified 44 patients with pure or mixed small cell cervical cancer who had undergone mutational analysis. Mutations had been detected using next generation sequencing of mutational hotspots in 50 cancer-related genes. Results Thirty-five mutations were identified in 24 patients (55%). Fifteen of these 24 patients (63%) had 1 mutation, 7 patients (29%) had 2 mutations, and 2 patients (8%) had 3 mutations. In all 44 patients, the most commonly seen mutations were mutations in PIK3CA (8 patients; 18%), KRAS (6 patients; 14%), and TP53 (5 patients; 11%). No other mutation was found in >7% of specimens. Of the 24 patients who had a mutation, 21 (88%) had at least 1 alteration for which there currently exists a class of biological agents targeting that mutation. In the entire cohort of 44 patients, 48% had at least 1 actionable mutation. Conclusion Although no single mutation was found in the majority of patients with small cell cervical cancer, almost half had at least 1 actionable mutation. As treatment options for patients with recurrent small cell cervical cancer are currently very limited, molecular testing for targetable mutations, which may suggest potential therapeutic strategies, may be useful for clinicians and patients.

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Section: Discussionmentioning

confidence: 99%

Sequencing of mutational hotspots in cancer-related genes in small cell neuroendocrine cervical cancer

Frumovitz

Burzawa

Byers

et al. 2016

Gynecologic Oncology

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“…In this scenario, the use of a cotargeting therapeutic strategy using cetuximab and PI3K or mTOR inhibitors as a first line of treatment may instead be ideal. In addition, human papillomavirus (HPV)–positive HNSCCs frequently harbor activating PIK3CA mutations (39,59,60) and exhibit aberrant mTOR activity (23), suggesting that this combined targeted therapy might be also useful in at least a subset of HPV-associated HNSCCs. Overall, we can conclude that the evaluation of mutations in genes encoding RAS and PIK3CA and/or other genetic and epigenetic alterations affecting the activity of the PI3K/AKT/mTOR pathway may predict the potential intrinsic resistance to cetuximab.…”

Section: Discussionmentioning

confidence: 99%

mTOR Co-Targeting in Cetuximab Resistance in Head and Neck Cancers Harboring PIK3CA and RAS Mutations

Wang

Martin

Molinolo

et al. 2014

JNCI: Journal of the National Cancer Institute

100

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BackgroundCetuximab, a monoclonal blocking antibody against the epidermal growth factor receptor EGFR, has been approved for the treatment of squamous cell carcinomas of the head and neck (HNSCC). However, only few patients display long-term responses, prompting the search for cetuximab resistance mechanisms and new therapeutic options enhancing cetuximab effectiveness.MethodsCetuximab-sensitive HNSCC cells were retro-engineered to express PIK3CA and RAS oncogenes. These cells and HNSCC cells harboring endogenous PIK3CA and RAS oncogenes were xenografted into mice (n = 10 per group) and studied for their biochemical, antitumor, antiangiogenic, and antilymphangiogenic responses to cetuximab and mTOR targeting agents. All P values are two-sided.ResultsCetuximab treatment of PIK3CA- and RAS-expressing HNSCC xenografts promoted an initial antitumor response, but all tumors relapsed within few weeks. In these tumors, cetuximab did not decrease the activity of mTOR, a downstream signaling target of EGFR, PIK3CA, and RAS. The combined administration of cetuximab and mTOR inhibitors exerted a remarkably increased antitumor activity, particularly in HNSCC cells that are resistant to cetuximab as a single agent. Indeed, cotargeting mTOR together with cetuximab caused a rapid tumor collapse of both PIK3CA- and RAS-expressing HNSCC xenografts (P < .001), concomitant with reduced proliferation (P < .001) and lymphangiogenesis (P < .001).ConclusionThe presence of PIK3CA and RAS mutations and other alterations affecting the mTOR pathway activity in HNSCC could be exploited to predict the potential resistance to cetuximab, and to select the patients that may benefit the most from the concomitant administration of cetuximab and PI3K and/or mTOR inhibitors as a precision molecular therapeutic option for HNSCC patients.

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“…The resulting data sets included 431 HPV-negative and 67 HPV-positive primary HNSCC samples with DNA mutation data and survival information for all but 1 of the HPV-negative HNSCC cases. Patients were stratified as never smokers or heavy smokers (>20 pack year history) based on similar research in the literature (18)(19)(20). Patients with between 1 and 20 pack years (n = 59), patients with no smoking history information (n = 10), and patients who were identified as current or former smokers but lacked pack year history information (n = 90) were excluded.…”

Section: Methodsmentioning

confidence: 99%

Mutational analysis of head and neck squamous cell carcinoma stratified by smoking status

Ghasemi¹,

Prokopec²,

MacNeil³

et al. 2019

JCI Insight

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High Frequency of Activating <emph type="ital">PIK3CA</emph> Mutations in Human Papillomavirus–Positive Oropharyngeal Cancer<alt-title><emph type="ital">PIK3CA</emph> in HPV+ Oropharyngeal Squamous Cell Carcinoma</alt-title>

Cited by 73 publications

References 17 publications

Sequencing of mutational hotspots in cancer-related genes in small cell neuroendocrine cervical cancer

Sequencing of mutational hotspots in cancer-related genes in small cell neuroendocrine cervical cancer

mTOR Co-Targeting in Cetuximab Resistance in Head and Neck Cancers Harboring PIK3CA and RAS Mutations

Mutational analysis of head and neck squamous cell carcinoma stratified by smoking status

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