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Gynecologic Cancer
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PI3K Pathway in Gynecologic Malignancies
Abstract
Alterations in PI3K signaling are common in gynecologic malignancies. Alterations detected vary with gynecologic cancer type, histologic subtypes within these, and clinical phenotypes. The distinction into type I and type II endometrial and ovarian carcinomas is reflected in distribution of changes detected in several of the PI3K members. PIK3CA mutations and amplifications are common in endometrial, ovarian, and cervical cancers. PTEN mutations and deletions are frequent in endometrial cancers. Several immunohistochemical studies of protein expression have explored these and other potential surrogate markers for PI3K pathway activation. Biomarkers to measure level of PI3K activity in clinical samples are not established. Whether amplifications, mutations, and deletions of the PI3K pathway members, and in particular change in their expression levels, result in clinically relevant pathway activation needs to be further explored. Also, to what extent these alterations drive the tumor behavior and are critical targets for therapeutics to improve patient survival needs to be further tested to establish predictive biomarkers for response to PI3K inhibition.
KEY POINTS
Alterations in PI3K signaling are common in gynecologic malignancies.
The type of alterations detected varies with histologic subtypes and clinical phenotypes.
PIK3CA mutations and amplifications, PTEN mutations and deletions, and immunohistochemical protein expression of these and other PI3K pathway members have been suggested as surrogate markers for PI3K pathway signaling.
Biomarkers to measure the level of PI3K activity in clinical samples have not been established.
Predictive biomarkers for response to PI3K inhibition have not been established.
The most frequent pelvic gynecologic malignancies are endometrial, ovarian, and cervical cancers, representing about 15% of all cancers and cancer-related deaths among women.1
Ovarian carcinoma is the most lethal, dominated by the epithelial type that is responsive to chemotherapy but seldom cured by chemotherapy.2 Attributed to cytoreductive surgery and combination chemotherapy with platinum and taxanes, 5-year survival is 45%, about a 10% increase over the last decades. Ovarian cancers are classified morphologically into subtypes according to their resemblance to normal gynecologic tissues: serous (fallopian tube), endometrioid (endometrium), mucinous (endocervical glands), and clear cell (glycogen rich vaginal nests). Using a low-grade and high-grade distinction, ovarian cancers may be classified as type I (20%), which includes all low-grade serous, low-grade endometrioid, mucinous, and clear cell tumors, and type II, which includes high-grade serous and endometrioid and undifferentiated tumors. Ovarian cancers are molecularly heterogeneous, to some extent reflected in this type I and type II distinction.
Endometrial cancer is the least lethal of the gynecologic malignancies. Approximately 75% of cases are diagnosed with the tumor confined to the uterine corpus.3 Despite this, 20% will recur after primary surgery and have limited response to systemic therapy. The categorization into two subtypes is the most common basis for determining risk of recurrence. The majority of cases are type I, associated with estrogen hyperstimulation and obesity, often endometrioid histology, low grade and stage, and associated with good prognosis. In contrast, type II cancers are characterized by high patient age, stage, and grade; nonendometrioid histology; and poor outcome.
For cervical cancers, the etiological role of infection with high-risk human papilloma viruses (HPV) is well established, with progression from persistent HPV infection through precancerous lesions to invasive cancer.4 This forms the basis for vaccination and screening programs to detect and treat precursor lesions, largely demonstrated to be successful in resource-rich countries. The dominating histologic subtypes are squamous cell carcinomas and adenocarcinomas, the latter being associated with poorer prognosis.
The phosphatidyl-inositide-3-kinases (PI3Ks) are a family of enzymes involved in cellular functions altered in cancer. The lipid kinases catalyze phosphorylation of phosphatidylinositol to activate signaling pathways regulating important cellular functions.5,6 Inappropriate cooperation of elements in the PI3K signaling has been shown to disrupt the regulation of cellular growth and proliferation, differentiation, motility, apoptosis, and intracellular trafficking (Fig. 1). Thus, large efforts are made to develop inhibitors of the PI3K pathway and molecular markers to predict response to such treatment in cancer.7
Fig 1. A schematic overview of the PI3K signaling cascade in the cell. PI3K signaling affects cell growth, proliferation, cell cycle regulation, and metabolism. Arrows indicate activation and bars inhibition.
Abbreviations: RTK, receptor tyrosine kinase; P, phosphate; PTEN, phosphatase and tensin homolog.
Three classes of PI3Ks with different isoforms within each class are identified. The class most implicated in cancer is the Class IA PI3Ks consisting of one regulatory and one catalytic subunit. The catalytic subunit PIK3CA (p110α) and regulatory subunit PIK3R1 (p85α) compose the heterodimer coupled to and activated by receptor tyrosine kinases (RTKs).6 Ligand binding to receptor tyrosine kinases (EGFR, HER2, VEGFR, FGFR2, IGF1R, PDGFR), leads to tyrosine phosphorylation of the intracellular receptor domain and activation of PI3K signaling. PI3K phosphorylates phosphatidylinositol-2-phosphate (PIP2) to PIP3. The tumor suppressor phosphatase and tensin homolog (PTEN) counteracts this by dephosphorylating PIP3 to PIP2. PIP3 propagates intracellular signaling by binding to AKT and the phosphoinositide dependent kinase 1 (PDK1). Ligand-independent activation of PI3K signaling is seen with specific somatic mutations of receptor tyrosine kinases or other PI3K pathway members rendering the pathway constitutively active.8 PI3K may also be activated by RAS (Fig. 1).
Both clinically and molecularly, ovarian cancer is a heterogeneous disease. Still, the increasingly used classification into types I and II ovarian cancers is also reflected in distinct molecular abnormalities evidenced by specific alterations in the PI3K signaling pathway among others.9,10
Around 70% of ovarian cancers show PI3K signaling activation attributed to a range of potential mechanisms.10 AKT2 and PIK3CA amplifications have been reported for all histologic subtypes.11 Activating mutations in PIK3CA is seen in up to 50% in endometrioid and clear cell subtypes.12,13 Loss of inhibition through inactivating mutations in PTEN, seen in 3% to 8% of the endometrioid and lower grade tumors, is also suggested to contribute to high PI3K signaling.12,14 Mechanisms for PI3K signaling activation is also presumed to involve autocrine and paracrine signaling through tyrosine kinase growth factor receptors.
Applying the type I and type II distinction, type I ovarian carcinomas are expressing IGFR, p53 wild-type, and have frequent activation mutations in RAS and PIK3CA as well as inactivating PTEN mutations.10,14 Type II cancers in contrast, are characterized by p53 mutations and a high level of genomic instability and inactivating aberrations in the BRCA genes.12 A range of chromosomal regions, of which several are potentially treatable with drugs, are found to be amplified in type II cancers, including regions harboring ERBB2, EGFR, PIK3CA, AKT1, and PIK3R1 (Table 1).
|
| Target | Alteration | EC - TYPE | OC - TYPE* | CC - TYPE | |||
|---|---|---|---|---|---|---|---|
| I (%) | II (%) | I (%) | II (%) | SCC (%) | AC (%) | ||
| ERBB2 | Amplification | 1 | 17 | H | 1 | 14 | 25 |
| FGFR2 | Mutation | 10–16 | 1 | <1 | |||
| PTEN inactivation | Mutation, deletion, methylation | 50 | 10 | 25 | <1 | 3 | 4 |
| AKT | Mutation | 3 | 0 | 3 | <1 | ||
| Amplification | <1 | 17 | |||||
| KRAS | Mutation | 11–26 | 2–4 | 30 | <1 | 3 | 14 |
| Amplification | 2 | 10 | <1 | 11 | |||
| PIK3CA | Mutation | 30 | 15 | 40 | <1 | 13 | 10 |
| Amplification | 2–14 | 46 | <1 | 17 | 60 | 80 | |
| PIK3R1 | Mutation | 43 | 12 | ||||
Abbreviations: EC, endometrial cancer; OC, ovarian cancer; CC, cervical cancer; SCC, squamous cell carcinoma; AC, adenocarcinoma.
* Type II ovarian cancer includes high-grade serous and endometrioid and undifferentiated tumors.
Furthermore, PI3K/AKT pathway activation has been linked to resistance to taxanes and platinum, and pathway inhibitors in combination with chemotherapy may be beneficial in these patients.15-17
Several players in the PI3K-signaling pathway are altered in endometrial cancer, suggesting PI3K/mTOR signaling as a key target for therapy in endometrial carcinomas. This is also reflected in ongoing clinical trials.3,18,19
The role of PI3K signaling in the biologically different type I and type II endometrial cancers is only partially understood (Table 1). Type I cancer is associated with hormone receptor positivity and FGFR2, KRAS, and PTEN mutations, yet amplifications are less common. Type II cancers in contrast are dominated by hormone receptor–negative tumors and harbors more often amplifications for the PIK3CA and ERBB2 regions, also found to predict poor outcome.19
PIK3CA mutations are found in both endometrioid and nonendometrioid cancers and have been linked to sustained proliferation in the disease. Mutations in PIK3R1 and PIK3R2, reported in endometrial cancer,20-22 have also been suggested as a novel mechanism for regulation of PTEN protein stability20 and to increase AKT activation.21
PTEN is frequently mutated in sporadic endometrial cancer, up to 80% reported for the endometrioid subtype. Mutations, deletions, promoter hypermethylation, and miRNA overexpression are all suggested mechanisms involved in the regulation of PTEN expression and function, also affecting PI3K signaling.18
Also, alterations in KRAS known to influence PI3K signaling are common in endometrial cancer.23 Activating KRAS mutations are more common in type I endometrial cancers, and, recently, KRAS gene amplification and overexpression, but not mutation, were found to associate with aggressive disease and increase from primary to metastatic endometrial cancer lesions.23
Recent studies have also suggested a link between estrogen receptor loss and PI3K activation in several independent patient cohorts, suggesting a rationale for investigating ER-alfa's potential to predict response to PI3K/mTOR inhibitors in clinical trials.24 Estradiol has been found to activate PI3K/AKT signaling in both an ER-alfa-dependent and independent manner.25
Among the gynecologic cancers, cervical cancer is the least studied regarding PI3K signaling. The region also harboring PIK3CA on chromosome 3q has been reported to influence the transition from severe dysplasia to invasive cancer of the uterine cervix.26 Also, molecular studies of the PI3K/AKT pathway in uterine cervical neoplasias have demonstrated frequent PIK3CA amplification and AKT phosphorylation.27
Also, studies have implicated the presence of somatic mutations relevant for PI3K signaling in PIK3CA, PTEN, and KRAS, the latter being more common in adenocarcinomas (Table 1).28
The receptor tyrosine kinase ERBB2 oncogene has been found to be amplified in squamous cell and even more frequent in adenocarcinomas of the uterine cervix,29 thus implicating another targetable and possible mechanism for activation of PI3K signaling in this disease. The human papillomavirus 16 E6 oncoprotein has also been reported to interfere with the insulin signaling pathway by binding to tuberin.30
Several alterations in pathway members of PI3K signaling have been reported to be present and relevant for phenotypes in ovarian, endometrial, and cervical cancers. Whether amplifications, mutations, and/or deletions of the pathway members and in particular the resulting changes in their expression levels, lead to clinically relevant pathway activation, needs to be further explored. Also, to what extent these alterations drive tumor behavior and are critical targets for therapeutics to improve patient survival demands further testing.28
Relationships are considered self-held and compensated unless otherwise noted. Relationships marked “L” indicate leadership positions. Relationships marked “I” are those held by an immediate family member; those marked “B” are held by the author and an immediate family member. Relationships marked “U” are uncompensated.
Employment or Leadership Position: None. Consultant or Advisory Role: None. Stock Ownership: None. Honoraria: None. Research Funding: Helga B. Salvesen, Roche. Expert Testimony: None. Other Remuneration: None.
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