- Email: [email protected]
IN5 Breast cancer in young women – genetic counseling and testing
S2
Invited Speakers’ Abstracts / The Breast 21S1 (2012) S1–S9
role of the microenvironment, (3) how does breast density and/or other factors (i.e. breast-feeding, parity) contribute to these findings and (4) will disparities in outcome persist in the era of modern targeted therapies – all areas deserving of further research.
Session II. Familial and hereditary breast cancer IN4 The biology of BRCA-associated breast cancer A. Tutt *. Breakthrough Breast Cancer Research Unit, Guy’s Hospital, Integrated Cancer Centre, King’s Health Partners AHSC London, UK BRCA1 and BRCA2 were cloned and sequenced over 15 years ago enabling an immediate change in the way in which women in high risk families could assess and manage their risk of future malignancy. The impact of functional analysis of the genes has been much slower to find clinical impact. These two genes have very large loci and open reading frames that encode complex and very different proteins. The understanding of their function has, and still does, challenge scientists over the last two decades. BRCA1 and BRCA2 both have function in the DNA damage response but their roles in this function, and consequences of loss, while overlapping can also be distinct. BRCA1 has wider roles within the DNA damage response than BRCA2 and also functions in gene transcription, chromatin modelling and breast cancer progenitor cell biology. In this lecture I will address the functions of these important genes in DNA repair explaining the processes of “homologous recombination” and “non homologous end joining” and why they matter to the mutation carrier. I will also touch on the broader functions of the genes. I will address: how the loss of these functions lead to an increase in frequency and earlier age of onset of breast cancer; How they define the phenotype of the associated cancers; How might this affect response to and toxicity of standard breast cancer therapies and the data that inform on the presence or absence of these effects; Finally I will revisit the original and persisting rationale for PARP inhibitors in BRCA mutation associated malignancy in distinction to unselected sporadic triple negative breast cancers and where these agents are now in the wake of the Iniparib triple negative breast cancer trials. IN5 Breast cancer in young women – genetic counseling and testing A.G. Arnold *. Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, USA About 5–10% of all breast cancer is thought to be hereditary. When a woman is diagnosed with breast cancer at a young age (i.e. under 40 years), we are concerned that she might have developed her cancer due to an inherited predisposition. Mutations in either BRCA1 or BRCA2 (Hereditary Breast and Ovarian Cancer Syndrome) are the most common definable cause of hereditary breast cancer, however, mutations in other genes such as p53 (Li-Fraumeni Syndrome), PTEN (Cowden Syndrome), and CDH1 (Hereditary Diffuse Gastric Cancer) are other cancer syndromes associated with early-onset breast cancer. In addition, mutations in low-penetrance genes such as PALB2 (“partner and localizer of BRCA2”), BRIP1, and CHEK2 have also been associated with an increased lifetime risk of breast cancer. Taking a detailed personal and family history of cancer is an integral part of the genetic risk assessment and helps guide which genetic test is the most appropriate for that individual and/or family. For example, as mentioned above, we suspect an inherited predisposition to breast cancer when a woman is diagnosed with breast cancer at a younger age than we would expect (i.e. diagnosed under 40 years). We are also suspicious when their tumors are “triple negative” (estrogen receptor negative, progesterone receptor
negative and HER2 negative) and/or they have bilateral or multifocal disease. Probably the most important part of the genetic risk assessment is determining if a patient has multiple first- and second-degree relatives diagnosed with breast and/or other cancers that might be seen in a particular cancer predisposition syndrome. Genetic counselors, geneticists and genetic nurse specialists are specifically trained to take detailed histories and decide which cancer predisposition syndrome/s should be looked for. Identification of cancer predisposition gene mutations in women with breast cancer can have significant clinical relevance. For example, it has been shown that BRCA1/2-deficient tumors appear to be especially responsive to new targeted therapies such as poly (ADP-ribose) polymerase (PARP) inhibitors. In addition, the patients’ risk for other cancers can be determined and the appropriate screening and/prevention recommendations provided (i.e. breast MRI, prophylactic bilateral salpingo-oophorectomy, mastectomy). Identifying detectable mutations in these women also provides important and necessary information for accurate cancer risk assessment of the patient’s close relatives. In this presentation we will review some of the genes involved in inherited breast cancer (high and low penetrance genes), the role of a cancer genetic counselor/geneticist/genetic nurse, how to make a genetic risk assessment, options for genetic testing and how genetic testing may affect reproductive decisions. We will also review the latest research into targeted therapy for women with BRCA1/2 gene mutations. Screening and follow up protocols for women at high risk for inherited breast cancer will also be discussed. IN6 Cancer risk-reducing measures for high risk women J.E. Garber *. Dana-Farber Cancer Institute, Boston, MA, USA Young women who learn they carry a mutation in a gene conferring a high risk of breast cancer must make a plan for managing their cancer risk over time. Today, there are several options for women, but unfortunately, all involve significant trade-offs. Increased surveillance: 6 large prospective studies have demonstrated that the sensitivity of mammograms is lower in young women with BRCA1/2 mutations, while the sensitivity of breast MRI is increased. The combination is effective, but whether it should be concurrent or separated by 6 months remains to be shown. Recent data suggest that the increased risk of radiation carcinogenesis should perhaps be a bigger concern among women initiating screening before ages 25–29, who should perhaps avoid significant diagnostic radiation until after age 30. There are still no data supporting ovarian surveillance. Prophylactic surgery: Prospective data confirms that prophylactic mastectomies reduce breast cancer risk by ~90%. Reconstruction options have improved, and uptake has increased. The availability of rapid turnaround testing has led to up-front testing at breast cancer diagnosis, which influences surgical decisions. Riskreducing salpingo-oophorectomy (RRSO) reduces ovarian cancer risk substantively, and, when performed in women before age 40–45, reduces breast cancer risk as well, especially in BRCA2 carriers. Early data on hormone replacement suggests that it does not increase breast cancer risk after RRSO. Nonetheless, the effects on quality of life are often challenging. The long term effects of early surgical menopause remain significant concerns for many women and physicians. The possibility of early salpingectomy without oophorectomy is intriguing, but not yet the standard of care. Chemoprevention: Limited data on tamoxifen shows effect in BRCA2 carriers. Oral contraceptives reduce ovarian cancer risk, but not yet sufficiently to justify deferring or foregoing RRSO. Other agents are in trials.
Invited Speakers’ Abstracts / The Breast 21S1 (2012) S1–S9
role of the microenvironment, (3) how does breast density and/or other factors (i.e. breast-feeding, parity) contribute to these findings and (4) will disparities in outcome persist in the era of modern targeted therapies – all areas deserving of further research.
Session II. Familial and hereditary breast cancer IN4 The biology of BRCA-associated breast cancer A. Tutt *. Breakthrough Breast Cancer Research Unit, Guy’s Hospital, Integrated Cancer Centre, King’s Health Partners AHSC London, UK BRCA1 and BRCA2 were cloned and sequenced over 15 years ago enabling an immediate change in the way in which women in high risk families could assess and manage their risk of future malignancy. The impact of functional analysis of the genes has been much slower to find clinical impact. These two genes have very large loci and open reading frames that encode complex and very different proteins. The understanding of their function has, and still does, challenge scientists over the last two decades. BRCA1 and BRCA2 both have function in the DNA damage response but their roles in this function, and consequences of loss, while overlapping can also be distinct. BRCA1 has wider roles within the DNA damage response than BRCA2 and also functions in gene transcription, chromatin modelling and breast cancer progenitor cell biology. In this lecture I will address the functions of these important genes in DNA repair explaining the processes of “homologous recombination” and “non homologous end joining” and why they matter to the mutation carrier. I will also touch on the broader functions of the genes. I will address: how the loss of these functions lead to an increase in frequency and earlier age of onset of breast cancer; How they define the phenotype of the associated cancers; How might this affect response to and toxicity of standard breast cancer therapies and the data that inform on the presence or absence of these effects; Finally I will revisit the original and persisting rationale for PARP inhibitors in BRCA mutation associated malignancy in distinction to unselected sporadic triple negative breast cancers and where these agents are now in the wake of the Iniparib triple negative breast cancer trials. IN5 Breast cancer in young women – genetic counseling and testing A.G. Arnold *. Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, USA About 5–10% of all breast cancer is thought to be hereditary. When a woman is diagnosed with breast cancer at a young age (i.e. under 40 years), we are concerned that she might have developed her cancer due to an inherited predisposition. Mutations in either BRCA1 or BRCA2 (Hereditary Breast and Ovarian Cancer Syndrome) are the most common definable cause of hereditary breast cancer, however, mutations in other genes such as p53 (Li-Fraumeni Syndrome), PTEN (Cowden Syndrome), and CDH1 (Hereditary Diffuse Gastric Cancer) are other cancer syndromes associated with early-onset breast cancer. In addition, mutations in low-penetrance genes such as PALB2 (“partner and localizer of BRCA2”), BRIP1, and CHEK2 have also been associated with an increased lifetime risk of breast cancer. Taking a detailed personal and family history of cancer is an integral part of the genetic risk assessment and helps guide which genetic test is the most appropriate for that individual and/or family. For example, as mentioned above, we suspect an inherited predisposition to breast cancer when a woman is diagnosed with breast cancer at a younger age than we would expect (i.e. diagnosed under 40 years). We are also suspicious when their tumors are “triple negative” (estrogen receptor negative, progesterone receptor
negative and HER2 negative) and/or they have bilateral or multifocal disease. Probably the most important part of the genetic risk assessment is determining if a patient has multiple first- and second-degree relatives diagnosed with breast and/or other cancers that might be seen in a particular cancer predisposition syndrome. Genetic counselors, geneticists and genetic nurse specialists are specifically trained to take detailed histories and decide which cancer predisposition syndrome/s should be looked for. Identification of cancer predisposition gene mutations in women with breast cancer can have significant clinical relevance. For example, it has been shown that BRCA1/2-deficient tumors appear to be especially responsive to new targeted therapies such as poly (ADP-ribose) polymerase (PARP) inhibitors. In addition, the patients’ risk for other cancers can be determined and the appropriate screening and/prevention recommendations provided (i.e. breast MRI, prophylactic bilateral salpingo-oophorectomy, mastectomy). Identifying detectable mutations in these women also provides important and necessary information for accurate cancer risk assessment of the patient’s close relatives. In this presentation we will review some of the genes involved in inherited breast cancer (high and low penetrance genes), the role of a cancer genetic counselor/geneticist/genetic nurse, how to make a genetic risk assessment, options for genetic testing and how genetic testing may affect reproductive decisions. We will also review the latest research into targeted therapy for women with BRCA1/2 gene mutations. Screening and follow up protocols for women at high risk for inherited breast cancer will also be discussed. IN6 Cancer risk-reducing measures for high risk women J.E. Garber *. Dana-Farber Cancer Institute, Boston, MA, USA Young women who learn they carry a mutation in a gene conferring a high risk of breast cancer must make a plan for managing their cancer risk over time. Today, there are several options for women, but unfortunately, all involve significant trade-offs. Increased surveillance: 6 large prospective studies have demonstrated that the sensitivity of mammograms is lower in young women with BRCA1/2 mutations, while the sensitivity of breast MRI is increased. The combination is effective, but whether it should be concurrent or separated by 6 months remains to be shown. Recent data suggest that the increased risk of radiation carcinogenesis should perhaps be a bigger concern among women initiating screening before ages 25–29, who should perhaps avoid significant diagnostic radiation until after age 30. There are still no data supporting ovarian surveillance. Prophylactic surgery: Prospective data confirms that prophylactic mastectomies reduce breast cancer risk by ~90%. Reconstruction options have improved, and uptake has increased. The availability of rapid turnaround testing has led to up-front testing at breast cancer diagnosis, which influences surgical decisions. Riskreducing salpingo-oophorectomy (RRSO) reduces ovarian cancer risk substantively, and, when performed in women before age 40–45, reduces breast cancer risk as well, especially in BRCA2 carriers. Early data on hormone replacement suggests that it does not increase breast cancer risk after RRSO. Nonetheless, the effects on quality of life are often challenging. The long term effects of early surgical menopause remain significant concerns for many women and physicians. The possibility of early salpingectomy without oophorectomy is intriguing, but not yet the standard of care. Chemoprevention: Limited data on tamoxifen shows effect in BRCA2 carriers. Oral contraceptives reduce ovarian cancer risk, but not yet sufficiently to justify deferring or foregoing RRSO. Other agents are in trials.