April 2015, Vol 4, No 2
Biomarkers of the mTOR Pathway in Breast CancerBreast Cancer
It is estimated that 232,670 women will have been diagnosed with breast cancer in 2014 and 40,000 women will have died of the disease. Approximately 89% of women with breast cancer of any stage will survive 5 years; when breast cancer is diagnosed at an early stage the prognosis is excellent, whereas the diagnosis of distant disease decreases the 5-year relative survival to about 25%.1
Currently, treatment of breast cancer is largely dictated by hormone receptor (HR) and HER2 status. Reliable biomarkers are needed to better guide treatment decisions and increase benefit while limiting toxicity. Gene expression profiling has helped us classify breast cancer into subtypes such as basal-like (usually corresponding to triple negative), ERBB2 positive (HER2 positive), normal breast-like, and luminal A and luminal B (HR positive).2-4 The Cancer Genome Atlas Network has identified the most frequent mutations associated with the above subtypes. The most common abnormalities seen in breast cancer are the loss of PTEN and PIK3CA mutations, commonly involving exons 9 and 20. More importantly, luminal and ERBB2-positive tumors are associated with the highest rate of PIK3CA mutations.5 However, the significance of these mutations in clinical practice and their use in finding druggable targets remain to be elucidated.
The Role of the mTOR Pathway in Breast Cancer
The PI3K/Akt/mTOR pathway is an intracellular network that plays a major role in cell growth and proliferation.6,7 PI3K is a heterodimer that belongs to the class IA of PI3Ks and consists of a catalytic (p110) and a regulatory (p85) subunit8; in response to nutrient availability or growth factor stimulation, the regulatory subunit interacts with proteins or receptors, and the catalytic subunit activates phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,4-trisphosphate (PIP3), thus leading to the phosphorylation of Akt, which is upstream of mTOR.9 PTEN acts as a tumor suppressor and mediates the opposite action (PIP3 to PIP2).10
mTOR is a serine/threonine protein kinase consisting of 2 complexes: mTORC1 (complex 1) and mTORC2 (complex 2). mTORC1 is the target of rapamycin and rapamycin analogs and is formed by the combination of raptor, mLST8, and proline-rich Akt substrate 40.11,12 Akt activates mTORC1 by inhibiting tuberous sclerosis complex 1/2 (TSC1/2), a tumor suppressor that acts as a GTP-ase activating protein for Rheb-GTP (Ras homolog enriched in brain-guanosine-5?-triphosphate).12,13 In turn, when activated, mTORC1 stimulates metabolism and inhibits apoptosis through S6K1 (40S ribosomal protein S6 kinase 1) and 4EBP1 (eukaryotic initiation factor 4E-binding protein)14-16 (Figure).
In HR-positive breast cancer, the mTOR pathway has been implicated in endocrine therapy resistance and both estrogen-dependent and estrogen-independent activation of estrogen receptor alpha.17 PTEN loss and constitutive activation of mTORC1 have been associated with intrinsic or acquired resistance to endocrine therapy, and the combination of endocrine agents with mTOR inhibitors can overcome this resistance in preclinical models.18,19
The activation of the mTOR pathway has also been associated with resistance to trastuzumab in HER2-overexpressing breast cancer.20 Oncogenic PIK3CA mutations or loss of PTEN has been linked to resistance to trastuzumab-based therapy and poor outcomes.21-23 Preclinical data combining the mTOR inhibitor everolimus with trastuzumab indicate that the combination is more effective in blocking cell growth compared with either agent alone.24
In the clinical setting, the BOLERO-2 study was a phase 3 randomized trial that evaluated everolimus in combination with exemestane in postmenopausal women with HR-positive, HER2-negative breast cancer.25 These patients had recurred or progressed on a nonsteroidal aromatase inhibitor. The study showed that the combination of mTOR inhibition with endocrine therapy significantly improved progression-free survival (PFS). The local assessment reported an improvement in PFS from 2.8 to 6.9 months (hazard ratio, 0.43; P <.001); the central assessment reported a PFS of 10.6 months in the combination arm versus 4.1 months in the exemestane-alone arm (hazard ratio, 0.36; P <.001). This study led to the FDA approval of everolimus for the treatment of metastatic, HR-positive breast cancer.
The TAMRAD trial was a phase 2, open-label trial that evaluated everolimus in combination with tamoxifen versus tamoxifen alone in patients with HR-positive breast cancer. The clinical benefit rate (CBR) and time to progression were significantly improved in the combination arm compared with tamoxifen (CBR, 61% vs 42%, respectively; P = .045).26
The BOLERO-3 trial evaluated everolimus in combination with cytotoxic therapy in patients with HER2-overexpressing advanced breast cancer with resistance to trastuzumab. This study showed that the addition of everolimus improved the PFS from 5.78 to 7 months (hazard ratio, 0.78; P = .0067). A central review and an adjudicated review that were done retrospectively revealed a hazard ratio of 0.88 and 0.85, respectively. The reported PFS improvement resulted mainly from the HR-negative subset of patients, patients who did not have visceral metastases, patients younger than 65 years, and patients who had received trastuzumab in the adjuvant or preoperative setting.27
These data indicate there might be a broader role for mTOR inhibitors in breast cancer, especially after the development of resistance to therapy. Multiple studies are ongoing, investigating the role of mTOR inhibitors in various settings.
Biomarkers Predicting Response
PIK3CA mutations and loss of PTEN are the most common aberrations found in breast cancer.5 It has been postulated that the presence of these abnormalities has prognostic value and can also predict response to therapeutics targeting the PI3K/Akt/mTOR pathway.
PIK3CA mutations are most frequently found in exons 9 and 20, which correspond to the helical (E542K and E545G) and kinase (H1047R) domains, respectively.28,29 PIK3CA mutations have been reported to be more common in lobular cancers, particularly exon 9 mutations, and HR-positive cancers.30 The impact of PIK3CA mutations on prognosis is unclear. In one study, the presence of PIK3CA mutations was not found to have correlation to clinical variables overall. However, when exon mutations were evaluated separately, exon 9 mutations were associated with worse overall survival (OS) and disease-free survival, whereas the opposite was observed in tissues with exon 20 mutations.31 Conversely, another analysis identified exon 20 mutations as an independent factor of poor survival in patients with breast cancer.32
One group also found an association between PIK3CA mutations and large tumor size (>2 cm) and positive node status; the presence of mutations was an independent predictor of worse survival in HER2-negative breast cancer.33
In a study of 547 human breast cancers and 41 cell lines, PIK3CA mutations were found more commonly in patients with either HR-positive or HER2-overexpressing tumors. The presence of PIK3CA mutations was not associated with long-term outcome after adjuvant endocrine therapy. However, PTEN loss predicted sensitivity to PI3K inhibitors in vitro.34
Breast cancer xenograft models were more sensitive to the PI3K inhibitor GDC-0941 when harboring PIK3CA mutations and HER2 amplification.35 Triple-negative breast cancer cells with activated PI3K/Akt signaling due to PIK3CA mutations or PTEN loss were more sensitive to PI3K/mTOR inhibition.36 The impact of PTEN loss on response to PI3K/mTOR inhibition is less consistent.37
A phase 1 study of PX-866, an oral irreversible PI3K inhibitor, in patients with advanced solid tumors demonstrated that patients who had PIK3CA mutations remained in the study longer than wild-type patients, although this difference was not statistically significant.38 In addition, Janku et al reported that patients with PIK3CA H1047R mutations had higher response rates compared with other PIK3CA mutations when treated with inhibitors of the PI3K/Akt/mTOR pathway. This effect was even more pronounced when patients were treated with a combination of agents as opposed to monotherapy.39
Biomarkers were also evaluated in the neoadjuvant trial of everolimus plus letrozole in patients with operable breast cancer.40 Tumors were sequenced for PIK3CA mutations in exons 9 and 20; a small number of patients who harbored mutations in the exon 9 helical domain had significantly improved response to the combination of everolimus plus letrozole versus letrozole alone, which may indicate a lack of sensitivity to endocrine treatment alone.
Molecular data derived from the TAMRAD trial showed that PI3K mutation status and PTEN and pAkt status did not associate with sensitivity or resistance to everolimus. However, patients with low PI3K and liver kinase B1 (LKB1) expression and high phospho-4E binding protein 1 (p4EBP1) had a better response. From these data, Treilleux et al concluded that tumors in which mTOR is activated in a manner independent of PI3K may benefit more from mTOR inhibition.41
Correlative studies of 227 tumor specimens from the BOLERO-2 study showed that the most common genetic alteration was a mutation in PIK3CA.25 The efficacy of everolimus was similar among PIK3CA wild-type and PIK3CA-mutated tumors.42 Similarly, genetic alterations of the PI3K pathway and amplification of cyclin D1 did not have any influence on the efficacy of everolimus; however, tumors with fibroblast growth factor receptor 1/2 alterations derived slightly less benefit from everolimus, although the number of patients was small. Additionally, tumors with zero to 1 genetic alteration derived greater benefit from everolimus than tumors with multiple aberrations. Twenty-four percent of the patients evaluated carried multiple genetic alterations, and these patients did not benefit from everolimus; thus, these patients can be considered for combination treatments as opposed to monotherapy.
Oliveira et al reported a retrospective analysis assessing the role of PI3K dysregulation as a predictor of treatment response in heavily pretreated patients with metastatic breast cancer. The study showed that while monotherapy with a PI3K/Akt/mTOR inhibitor had limited benefit, combination of an inhibitor with endocrine therapy, HER2-directed agent, or chemotherapy in patients with PIK3CA mutations led to an increased time to progression compared with wild-type tumors.43 In this study, PTEN status did not correlate with clinical outcome.
pS6K (S6 Kinase), pAkt
The activation of Akt has been associated with endocrine resistance and poor outcomes in breast cancer patients.44,45 High levels of pS6K and pAkt are associated with the constitutive activation of the mTOR pathway and predict a response to rapamycin analogs in breast cancer cell lines.46 This is independent of PTEN status. Similarly, increased levels of pAkt, GSK3?, and TSC2 also correlated with sensitivity to everolimus.47
INPP4B is a tumor suppressor that negatively regulates the PI3K/Akt pathway.48 Loss or knockdown of INPP4B activates the PI3K/Akt pathway and leads to tumor growth and increased cell motility.49 This loss can often be seen in PTEN-null tumors or basal-like breast cancer tumors, and it correlates with worse clinical outcomes.50 These tumors may be candidates for PI3K/Akt/mTOR inhibition.
Several preclinical models have demonstrated that HER2 status also correlates with response to inhibitors of the mTOR pathway.37,51 This is probably due to the activation of pAkt, which is downstream of HER2.46,52,53
A phase 2 study by Ellard et al that evaluated various dosing regimens of everolimus in breast cancer patients failed to find a correlation between clinical response and biomarkers.54 It is possible that the small number of patients, the variability of the tumors, and the techniques used influenced these results. It is also possible that mutations within the helical versus kinase domain of
PIK3CA impact function differently and may need to be evaluated separately among patients treated with inhibitors of the mTOR pathway.
Finally, a meta-analysis that included 17 clinical studies in various solid tumors showed that the activation of the PI3K/Akt/mTOR pathway was linked to worse 5-year survival (odds ratio [OR] 2.12; P <.001). Six studies assessing PIK3CA mutations showed no association with survival (OR 1.24; P = .46). However, studies evaluating activated mTOR/Akt and PTEN loss identified a significant connection with worse survival (P = .01 and P <.001, respectively).55
In summary, there are data, mainly derived from preclinical models, supporting that the activation of the PI3K/Akt/mTOR pathway, regardless of the inciting factor, can predict response to rapamycin analogs and other inhibitors of the pathway. However, clinical trial data to date have not been conclusive regarding the prognostic and predictive value of biomarkers of the mTOR pathway.
Biomarkers Predicting Resistance
PIK3CA mutations frequently coexist with KRAS mutations, the presence of which has been associated with worse outcomes and shorter OS.56,57 In xenograft models, Ihle et al showed that the presence of oncogenic Ras mutations conferred resistance to PI3K inhibition regardless of PIK3CA and PTEN status.58 Di Nicolantonio et al also showed that cancer cells with PIK3CA mutations and PTEN loss were more sensitive to everolimus; however, this response was abrogated when these aberrations were combined with KRAS or BRAF mutations.59 These data suggest that the presence of KRAS mutations may require targeting of both pathways for optimal tumor suppression.
However, an evaluation of breast and gynecologic tumors for PIK3CA and KRAS/BRAF mutations failed to show an impact of KRAS/BRAF status on response to treatment, although the number of patients was small.60 In a retrospective study, the same group reported that among patients treated with PI3K/Akt/mTOR inhibitors, the coexistence of PIK3CA and KRAS mutations (in codons 12 and 13) was associated with lower response rates.39 The number of patients in both studies was small, and the results should be interpreted with caution.
Other biomarkers of resistance demonstrated in breast cancer cell lines include activation of NOTCH and induction of c-MYC.61 The clinical significance of these biomarkers is currently uncertain but warrants further investigation.
Mutations of PIK3CA and loss of PTEN are among the most frequent aberrations in breast cancer. Even though preclinical data have suggested that these alterations could predict response to therapeutic agents, correlative data from clinical studies have failed to verify this association.
Newer biomarkers, such as LKB1 and 4EBP1 expression, may be worth exploring. Additionally, a recently described PI3K/mTOR gene signature (PIK3CA-GS) may be a more reliable indicator of pathway activation and may help identify patients who will benefit from everolimus and other inhibitors of the pathway.62,63 It is possible that patients with multiple genetic aberrations could benefit from the combination of targeted agents.
Finally, the overall interpretation of the data is limited by the small sample sizes of clinical trials. Correlative studies from large prospective studies will be needed to identify patients who will benefit from PI3K/Akt/mTOR inhibition.
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- Andre F, Campone M, O’Regan R, et al. Phase I study of everolimus plus weekly paclitaxel and trastuzumab in patients with metastatic breast cancer pretreated with trastuzumab. J Clin Oncol. 2010;28:5110-5115.
- Berns K, Horlings HM, Hennessy BT, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12:395-402.
- Nagata Y, Lan KH, Zhou X, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004;6:117-127.
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- Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366:520-529.
- Bachelot T, Bourgier C, Cropet C, et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol. 2012;30:2718-2724.
- Andre F, O’Regan R, Ozguroglu M, et al. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2014;15:580-591.
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- Janku F, Wheler JJ, Naing A, et al. PIK3CA mutation H1047R is associated with response to PI3K/AKT/mTOR signaling pathway inhibitors in early-phase clinical trials. Cancer Res. 2013;73:276-284.
- Baselga J, Semiglazov V, van Dam P, et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol. 2009;27:2630-2637.
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- Hortobagyi GN, Piccart-Gebhart MJ, Rugo HS, et al. Correlation of molecular alterations with efficacy of everolimus in hormone receptor–positive, HER2-negative advanced breast cancer: results from BOLERO-2. J Clin Oncol. 2013;31(suppl). Abstract LBA509.
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Dr Paplomata is Assistant Professor, Department of Hematology and Medical Oncology at Emory University School of Medicine. Her research focus is on mechanisms of resistance in breast cancer. She has participated in basic science research and translational research on mechanisms of resistance to HER2-directed therapies and chemotherapy.
Dr Zelnak is Assistant Professor, Department of Hematology and Medical Oncology at Emory University School of Medicine. She has published in the area of breast cancer research and has been an invited speaker at multiple national conferences on early-stage, triple-negative, and metastatic breast cancer.
Dr O’Regan is Professor and Vice Chair for Educational Affairs of Hematology and Medical Oncology at Emory University School of Medicine, Director of Translational Breast Cancer Research at Winship Cancer Institute of Emory University, Louisa and Rand Glenn Family Chair in Breast Cancer Research at Glenn Family Breast Center, and Chief of Service for Hematology and Medical Oncology at Georgia Cancer Center for Excellence at Grady Memorial Hospital.
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