- Email: [email protected]
PG 5.03 Targeting PIK3CA pathway
S10
Speakers’ Abstracts / The Breast 24S1 (2015) S1–S25
It has long been recognised that there is an association between familial predisposition to breast cancer and the Triple Negative Breast Cancer (TNBC). This is driven by the specific enrichment for TNBC in the breast cancers arising in BRCA1 mutation carriers. Loss of function of BRCA1 or BRCA2 leads to impairment of an accurate DNA repair process called Homologous Recombination (HR) used by proliferating cells to repair DNA replication forks that encounter spontaneous or therapeutic damage in DNA. Failure of HR causes a high degree of genome instability that can have distinctive features driven by the cell’s need to use other DNA repair processes. HR is used to repair damage caused by certain forms of chemotherapy including that caused by platinum salts. This leads to high levels of platinum cell kill in preclinical studies of BRCA1 and BRCA2 mutation. Recently the use of PARP inhibitors has been shown to kill malignant cells with deficient HR, such as those with BRCA1 and BRCA2 mutation, through “synthetic lethality”. A wider group of genes is known to have function in the homologous recombination and the DNA replication stress response pathways and many of these are also known to be breast cancer predisposition alleles. Recent studies and some clinical trials have begun to address whether the specific defects in DNA repair that underlie BRCA1/2 associated breast cancer and sub-populations within sporadic breast cancer may lead to sensitivity to platinum salts and PARP inhibitors. Other kinases such as ATR, CHK1 and PI3-kinase may also form therapeutic targets that modify the DNA damage response and of which could be combined with PARP inhibition or platinum salts. I will review the biological mechanisms relevant to these approaches within specific breast cancer types. I will also review relevant clinical trials that have recently reported, and highlight others that are on going and discuss some emerging companion diagnostic approaches that seek to identify breast cancers that have deficiencies in HR and might benefit from platinum or DNA repair inhibitor therapies. Disclosure of Interest: Grants/research support: Vertex, AstraZeneca, Myriad Genetics, Roche. Honoraria/consultation fees: Vertex, Eisai. Other: Named on Patent (KCL) Genome Instability Scars as biomarkers of DNA damage defects. ICR Rewards to inventors scheme – PARP inhibitors. PG 5.03 Targeting PIK3CA pathway J. Baselga *. Memorial Sloan Kettering Cancer Center, Memorial Sloan-Kettering Cancer Center, New York, United States of America Pharmacologic and genetic evidences point to the PI3K/AKT/mTOR pathway as a key mediator of oncogenic signaling in breast cancer. PIK3CA, the gene encoding for p110a, is frequently mutated in human cancers. In particular, hot spot mutations of this gene reside in the helical (E542K and E545K) or catalytic (H1047R) domains are found in over a third of estrogen receptor (ER)-positive breast cancer, representing the most common genomic alteration in this group of tumors. Direct pharmacologic inhibition of the PI3K/AKT/mTOR signaling is, therefore, an attractive clinical strategy for breast cancer. In addition to mTOR inhibitors already approved for the therapy of patients with advanced ER+ breast cancer, there are now a number of additional experimental agents that are in clinical development including pan-PI3K inhibitors. Among them, Buparlisib is a panPI3K inhibitor that is being studied in two large phase III studies in combination with fulvestrant in patients with advanced disease. More recently, PI3Ka specific inhibitors have shown remarkable clinical activity in the phase I setting in patients with breast tumors that harbor PI3Ka mutations and these agents are also entering now phase III studies in combination with hormonal therapies. The underlying reason to study these agents in combination with hormonal therapies is compelling. Given that the vast majority of PIK3CA-mutant tumors are ER-positive, it is plausible to hypothesize
that both pathways can drive proliferation and survival in these cells. A tangible evidence that the PI3K and ER pathways can cooperate in tumor progression came from the Bolero 2 study that showed an impressive improvement in progression-free survival (PFS) in ERpositive breast cancer patients treated with the mTOR inhibitor everolimus in combination with the anti-estrogen aromatase inhibitor exemestane. These patients had failed prior endocrine therapy and taking in consideration that activity of single agent mTOR inhibitors is minimal, these results suggest an interaction between mTOR and ER. In addition, it is known that anti-estrogen therapy induces the activation of the PI3K pathway in vitro and we have also observed that PI3K inhibition results in a powerful activation of ER signaling. In summary, there is ample evidence that PI3K inhibition will be a fruitful approach in the treatment of patients with advanced breast cancer and it is likely that determining the presence of PI3Ka mutations in breast cancer will become useful in the daily clinical practice. The results of the ongoing phase III studies will further delineate the role of these agents in the therapy of breast cancer. Disclosure of Interest: Consultant/Advisor: Novartis, Verastem, Roche, Juno, Infinity. PG 5.04 Targeting FGFR pathway N. Turner *. Breast Unit, Royal Cancer Hospital, London, United Kingdom The Fibroblast Growth Factor Receptors can be activated by diverse mechanisms in breast cancer, including amplification of FGFR1 and FGFR2, rare activating mutations and translocations, as well as potentially through aberrant ligand dependent signaling. Amplification of FGFR1 occurs in 10% of ER positive cancer, enriched in luminal B type breast cancer, with FGFR1 amplification associating with increased risk of relapse. A number of early phase clinical trials have selected breast cancers with FGFR1 amplification, providing preliminary evidence of activity for small molecule FGFR inhibitors in FGFR1 amplified breast cancer. The preclinical and clinical data will be reviewed, and prospects for later stage clinical development of FGFR inhibitors discussed. Disclosure of Interest: Grants/research support: AstraZeneca, Pfizer. Honoraria or consultation fees: Novartis, Roche, AstraZeneca, Servier, Clovis, Astellas, Tesaro, Genomic Health.
Thursday, 19 March 2015
14.00–15.00
Session 6: Primary prevention, metabolism and genetics PG 6.01 Using germline genetics in the management of breast cancer patients and their families J. Garber *. Center for Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, United States of America A subset of women with breast cancer carry a heritable predisposing mutation in a breast cancer susceptibility gene that may underlie the development of their breast cancer. There are a number of circumstances in which a woman’s BRCA mutation status may now affect decisions about her care, over and above the implications for the management of breast, ovarian and other cancer risk in family members, for whom data continues to show an advantage for intensified breast cancer surveillance and risk reducing preventive surgeries. These include:
Speakers’ Abstracts / The Breast 24S1 (2015) S1–S25
It has long been recognised that there is an association between familial predisposition to breast cancer and the Triple Negative Breast Cancer (TNBC). This is driven by the specific enrichment for TNBC in the breast cancers arising in BRCA1 mutation carriers. Loss of function of BRCA1 or BRCA2 leads to impairment of an accurate DNA repair process called Homologous Recombination (HR) used by proliferating cells to repair DNA replication forks that encounter spontaneous or therapeutic damage in DNA. Failure of HR causes a high degree of genome instability that can have distinctive features driven by the cell’s need to use other DNA repair processes. HR is used to repair damage caused by certain forms of chemotherapy including that caused by platinum salts. This leads to high levels of platinum cell kill in preclinical studies of BRCA1 and BRCA2 mutation. Recently the use of PARP inhibitors has been shown to kill malignant cells with deficient HR, such as those with BRCA1 and BRCA2 mutation, through “synthetic lethality”. A wider group of genes is known to have function in the homologous recombination and the DNA replication stress response pathways and many of these are also known to be breast cancer predisposition alleles. Recent studies and some clinical trials have begun to address whether the specific defects in DNA repair that underlie BRCA1/2 associated breast cancer and sub-populations within sporadic breast cancer may lead to sensitivity to platinum salts and PARP inhibitors. Other kinases such as ATR, CHK1 and PI3-kinase may also form therapeutic targets that modify the DNA damage response and of which could be combined with PARP inhibition or platinum salts. I will review the biological mechanisms relevant to these approaches within specific breast cancer types. I will also review relevant clinical trials that have recently reported, and highlight others that are on going and discuss some emerging companion diagnostic approaches that seek to identify breast cancers that have deficiencies in HR and might benefit from platinum or DNA repair inhibitor therapies. Disclosure of Interest: Grants/research support: Vertex, AstraZeneca, Myriad Genetics, Roche. Honoraria/consultation fees: Vertex, Eisai. Other: Named on Patent (KCL) Genome Instability Scars as biomarkers of DNA damage defects. ICR Rewards to inventors scheme – PARP inhibitors. PG 5.03 Targeting PIK3CA pathway J. Baselga *. Memorial Sloan Kettering Cancer Center, Memorial Sloan-Kettering Cancer Center, New York, United States of America Pharmacologic and genetic evidences point to the PI3K/AKT/mTOR pathway as a key mediator of oncogenic signaling in breast cancer. PIK3CA, the gene encoding for p110a, is frequently mutated in human cancers. In particular, hot spot mutations of this gene reside in the helical (E542K and E545K) or catalytic (H1047R) domains are found in over a third of estrogen receptor (ER)-positive breast cancer, representing the most common genomic alteration in this group of tumors. Direct pharmacologic inhibition of the PI3K/AKT/mTOR signaling is, therefore, an attractive clinical strategy for breast cancer. In addition to mTOR inhibitors already approved for the therapy of patients with advanced ER+ breast cancer, there are now a number of additional experimental agents that are in clinical development including pan-PI3K inhibitors. Among them, Buparlisib is a panPI3K inhibitor that is being studied in two large phase III studies in combination with fulvestrant in patients with advanced disease. More recently, PI3Ka specific inhibitors have shown remarkable clinical activity in the phase I setting in patients with breast tumors that harbor PI3Ka mutations and these agents are also entering now phase III studies in combination with hormonal therapies. The underlying reason to study these agents in combination with hormonal therapies is compelling. Given that the vast majority of PIK3CA-mutant tumors are ER-positive, it is plausible to hypothesize
that both pathways can drive proliferation and survival in these cells. A tangible evidence that the PI3K and ER pathways can cooperate in tumor progression came from the Bolero 2 study that showed an impressive improvement in progression-free survival (PFS) in ERpositive breast cancer patients treated with the mTOR inhibitor everolimus in combination with the anti-estrogen aromatase inhibitor exemestane. These patients had failed prior endocrine therapy and taking in consideration that activity of single agent mTOR inhibitors is minimal, these results suggest an interaction between mTOR and ER. In addition, it is known that anti-estrogen therapy induces the activation of the PI3K pathway in vitro and we have also observed that PI3K inhibition results in a powerful activation of ER signaling. In summary, there is ample evidence that PI3K inhibition will be a fruitful approach in the treatment of patients with advanced breast cancer and it is likely that determining the presence of PI3Ka mutations in breast cancer will become useful in the daily clinical practice. The results of the ongoing phase III studies will further delineate the role of these agents in the therapy of breast cancer. Disclosure of Interest: Consultant/Advisor: Novartis, Verastem, Roche, Juno, Infinity. PG 5.04 Targeting FGFR pathway N. Turner *. Breast Unit, Royal Cancer Hospital, London, United Kingdom The Fibroblast Growth Factor Receptors can be activated by diverse mechanisms in breast cancer, including amplification of FGFR1 and FGFR2, rare activating mutations and translocations, as well as potentially through aberrant ligand dependent signaling. Amplification of FGFR1 occurs in 10% of ER positive cancer, enriched in luminal B type breast cancer, with FGFR1 amplification associating with increased risk of relapse. A number of early phase clinical trials have selected breast cancers with FGFR1 amplification, providing preliminary evidence of activity for small molecule FGFR inhibitors in FGFR1 amplified breast cancer. The preclinical and clinical data will be reviewed, and prospects for later stage clinical development of FGFR inhibitors discussed. Disclosure of Interest: Grants/research support: AstraZeneca, Pfizer. Honoraria or consultation fees: Novartis, Roche, AstraZeneca, Servier, Clovis, Astellas, Tesaro, Genomic Health.
Thursday, 19 March 2015
14.00–15.00
Session 6: Primary prevention, metabolism and genetics PG 6.01 Using germline genetics in the management of breast cancer patients and their families J. Garber *. Center for Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, United States of America A subset of women with breast cancer carry a heritable predisposing mutation in a breast cancer susceptibility gene that may underlie the development of their breast cancer. There are a number of circumstances in which a woman’s BRCA mutation status may now affect decisions about her care, over and above the implications for the management of breast, ovarian and other cancer risk in family members, for whom data continues to show an advantage for intensified breast cancer surveillance and risk reducing preventive surgeries. These include: