- Email: [email protected]
PG 6.01 Using germline genetics in the management of breast cancer patients and their families
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:
14th St.Gallen International Breast Cancer Conference / The Breast 24S1 (2015) S1–S25
1. The higher risk of second primary cancer may affect decisions in BRCA carriers about primary surgical option: breast conservation vs. bilateral mastectomies. 2. The SOFT data show the advantage of ovarian suppression plus hormonal therapy in premenopausal women requiring chemotherapy in treatment of their hormone receptor positive tumors. BRCA carriers would more likely undergo risk-reducing bilateral salpingo-oophorectomies rather than LHRH-agonist therapy. 3. Data from two neoadjuvant trials in triple negative breast cancer (GeparSEXTO and Alliance 4003) show an advantage for the use of platinum in BRCA carriers: The TNT trial shows a similar advantage in metastatic disease. Additional tumor biomarkers may predict response better than BRCA1/2 mutation status. 4. BRCA1/2 mutation carriers are eligible for the BIG/NRG adjuvant parp inhibitor trial, OlympiA, and other neoadjuvant trials. 5. BRCA mutation status may affect interventions to reduce the risk of additional primary cancers of the ovary (RRSO) and melanoma. Family members may use the information to reduce their risks of breast cancer, ovarian cancer, prostate cancer and possibly pancreatic cancer. Mechanisms of acquired resistance against therapies targeting the DNA repair pathways are emerging. In addition, genetic testing now frequently includes evaluation of additional genes that have been associated with increased breast cancer risk, including TP53, PTEN, STK11, and CDH1, as well as an expanding group of moderate penetrance genes. Many women are now offered panels of genes for assessment of their risk either as a comprehensive germline test or following a negative BRCA1/2 examination. These genes do not yet affect treatment options, but may be used to assess risk of additional primary tumors and options for reducing those risks. These data suggest that women with early onset breast cancer, triple negative breast cancers and other features suggesting hereditary predisposition underlying the diagnosis should consider genetic evaluation. The results may affect their own breast cancer care, and the cancer risk assessment among their family members. Disclosure of Interest: Grants/research support: Myriad Genetics, Novartis (self); Novartis, Pfizer (spouse). Honoraria or consultation fees: Novartis, Pfizer (spouse); Pfizer (self). PG 6.02 Preventing invasive breast cancer in women at high risk based on benign/in situ pathology J. Cuzick *, M. Thorat. Centre for Cancer Prevention, Queen Mary University of London, London, United Kingdom There are three main ways in which women can be identified as being at high risk of breast cancer: (i) family history of breast and/or ovarian cancer, which includes genetic factors, (ii) mammographically identified high breast density, and (iii) certain types of benign breast disease. The last category is the least common, but in some ways the easiest one for which treatment can be offered, because these women have already entered into the treatment system. Not all types of benign breast disease are associated with increased risk. The highest risk is seen in women with lobular carcinoma in situ, but this is very rare. More common is atypical hyperplasia, which comprises about 5–10% biopsied lesions and carries a 4–5 relative risk of subsequent breast cancer. It is most often an incidental finding when micro calcifications are seen on a mammogram. More common is hyperplasia of the usual type which is typically defined as breast duct epithelium thickness four or more cells deep and displaying admixture of two or more cell types; epithelial, myoepithelial and/or metaplastic apocrine cells. It carries a roughly twofold increase risk. Other types of benign lesions, notably about 50% of fibroadenomas and biopsied breast cysts which do not display hyperplasia, do not carry an increased
S11
risk of breast cancer. However women with aspirated cysts (and no histology) are also at increased risk of subsequent breast cancer. Tamoxifen has been shown to be particularly effective in preventing subsequent breast cancer in women with atypical hyperplasia – with a more than 70% reduction in the P1 trial and a 60% reduction in IBIS I. No data specific to atypical hyperplasia are available for the other two tamoxifen prevention trials. The aromatase inhibitors also are highly effective for atypical hyperplasia, with somewhat larger risk reductions than for other high risk women. There are no published data on the effectiveness of tamoxifen or the aromatase inhibitors for breast cancer prevention in women with hyperplasia of the usual type, or for women with aspirated cysts. A full review of breast cancer risk for different types of benign breast disease and the impact of preventive therapy in women with atypical hyperplasia and hyperplasia of the usual type will be presented. Disclosure of Interest: Prof. Cuzick has received research funding from Astra Zeneca and is their advisory board member. PG 6.03 Obesity and insulin resistance: clinical relevance and research priorities P.J. Goodwin *. University of Toronto, Mount Sinai Hospital, Toronto, Canada There is growing recognition that obesity is associated with adverse breast cancer outcomes. Research since St. Gallen 2013 has focused on four key areas, discussed below. 1. Is obesity associated with poor outcomes in all biologic subtypes of breast cancer? A recent meta-analysis provides evidence for an adverse association in estrogen receptor (ER) positive and negative BC. Some, but not all, subsequent analyses (many embedded in RCTs, including one by the Oxford Overview) suggest associations may be restricted to ER positive BC. Patient selection (e.g. exclusion of women with cardiac risk factors associated with insulin resistance/obesity) leading to exclusion of metabolically unhealthy women from RCTs, and other factors, may have contributed to these inconsistencies. 2. Does obesity impact AI efficacy or estrogen suppression in the adjuvant setting? Obesity is an adverse prognostic factor in women receiving letrozole or anastrozole; the relative benefit of anastrozole (but not letrozole) vs tamoxifen may be lowered in obese women. Emerging data suggest that endogenous estrogen suppression by AIs may be somewhat less complete in obese women; data are inconsistent and the clinical significance of these observations is unclear; for instance, one report suggests benefits of extended adjuvant anastrozole may be limited to normal weight women. 3. What are the potential biologic underpinnings of the obesity– breast cancer association? Components of the insulin resistance syndrome (hyperinsulinemia, dysglycemia, inflammation, altered adipokine profile) as well as obesity associated elevations in endogenous estrogen levels have been proposed as potential biologic mediators. The biology is likely complex, with the relative importance of different mediators varying across BC subtypes and over time (e.g. we found insulin to be important in the first 5 years after diagnosis while obesity and leptin associations persisted beyond 5 years). 4. Are interventions studies warranted? If so, which interventions in which populations? In the 45 years since the obesitybreast cancer prognosis association was first reported, dozens of observational studies have confirmed an adverse association, without identifying consistent subgroup patterns. It is not clear whether this association is causal, nor is it clear that reducing weight/improving metabolism will improve prognosis (ie: obesity effects may be “built into” BC biology and not be responsive to changes in weight or metabolism). The WINS RCT suggested
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:
14th St.Gallen International Breast Cancer Conference / The Breast 24S1 (2015) S1–S25
1. The higher risk of second primary cancer may affect decisions in BRCA carriers about primary surgical option: breast conservation vs. bilateral mastectomies. 2. The SOFT data show the advantage of ovarian suppression plus hormonal therapy in premenopausal women requiring chemotherapy in treatment of their hormone receptor positive tumors. BRCA carriers would more likely undergo risk-reducing bilateral salpingo-oophorectomies rather than LHRH-agonist therapy. 3. Data from two neoadjuvant trials in triple negative breast cancer (GeparSEXTO and Alliance 4003) show an advantage for the use of platinum in BRCA carriers: The TNT trial shows a similar advantage in metastatic disease. Additional tumor biomarkers may predict response better than BRCA1/2 mutation status. 4. BRCA1/2 mutation carriers are eligible for the BIG/NRG adjuvant parp inhibitor trial, OlympiA, and other neoadjuvant trials. 5. BRCA mutation status may affect interventions to reduce the risk of additional primary cancers of the ovary (RRSO) and melanoma. Family members may use the information to reduce their risks of breast cancer, ovarian cancer, prostate cancer and possibly pancreatic cancer. Mechanisms of acquired resistance against therapies targeting the DNA repair pathways are emerging. In addition, genetic testing now frequently includes evaluation of additional genes that have been associated with increased breast cancer risk, including TP53, PTEN, STK11, and CDH1, as well as an expanding group of moderate penetrance genes. Many women are now offered panels of genes for assessment of their risk either as a comprehensive germline test or following a negative BRCA1/2 examination. These genes do not yet affect treatment options, but may be used to assess risk of additional primary tumors and options for reducing those risks. These data suggest that women with early onset breast cancer, triple negative breast cancers and other features suggesting hereditary predisposition underlying the diagnosis should consider genetic evaluation. The results may affect their own breast cancer care, and the cancer risk assessment among their family members. Disclosure of Interest: Grants/research support: Myriad Genetics, Novartis (self); Novartis, Pfizer (spouse). Honoraria or consultation fees: Novartis, Pfizer (spouse); Pfizer (self). PG 6.02 Preventing invasive breast cancer in women at high risk based on benign/in situ pathology J. Cuzick *, M. Thorat. Centre for Cancer Prevention, Queen Mary University of London, London, United Kingdom There are three main ways in which women can be identified as being at high risk of breast cancer: (i) family history of breast and/or ovarian cancer, which includes genetic factors, (ii) mammographically identified high breast density, and (iii) certain types of benign breast disease. The last category is the least common, but in some ways the easiest one for which treatment can be offered, because these women have already entered into the treatment system. Not all types of benign breast disease are associated with increased risk. The highest risk is seen in women with lobular carcinoma in situ, but this is very rare. More common is atypical hyperplasia, which comprises about 5–10% biopsied lesions and carries a 4–5 relative risk of subsequent breast cancer. It is most often an incidental finding when micro calcifications are seen on a mammogram. More common is hyperplasia of the usual type which is typically defined as breast duct epithelium thickness four or more cells deep and displaying admixture of two or more cell types; epithelial, myoepithelial and/or metaplastic apocrine cells. It carries a roughly twofold increase risk. Other types of benign lesions, notably about 50% of fibroadenomas and biopsied breast cysts which do not display hyperplasia, do not carry an increased
S11
risk of breast cancer. However women with aspirated cysts (and no histology) are also at increased risk of subsequent breast cancer. Tamoxifen has been shown to be particularly effective in preventing subsequent breast cancer in women with atypical hyperplasia – with a more than 70% reduction in the P1 trial and a 60% reduction in IBIS I. No data specific to atypical hyperplasia are available for the other two tamoxifen prevention trials. The aromatase inhibitors also are highly effective for atypical hyperplasia, with somewhat larger risk reductions than for other high risk women. There are no published data on the effectiveness of tamoxifen or the aromatase inhibitors for breast cancer prevention in women with hyperplasia of the usual type, or for women with aspirated cysts. A full review of breast cancer risk for different types of benign breast disease and the impact of preventive therapy in women with atypical hyperplasia and hyperplasia of the usual type will be presented. Disclosure of Interest: Prof. Cuzick has received research funding from Astra Zeneca and is their advisory board member. PG 6.03 Obesity and insulin resistance: clinical relevance and research priorities P.J. Goodwin *. University of Toronto, Mount Sinai Hospital, Toronto, Canada There is growing recognition that obesity is associated with adverse breast cancer outcomes. Research since St. Gallen 2013 has focused on four key areas, discussed below. 1. Is obesity associated with poor outcomes in all biologic subtypes of breast cancer? A recent meta-analysis provides evidence for an adverse association in estrogen receptor (ER) positive and negative BC. Some, but not all, subsequent analyses (many embedded in RCTs, including one by the Oxford Overview) suggest associations may be restricted to ER positive BC. Patient selection (e.g. exclusion of women with cardiac risk factors associated with insulin resistance/obesity) leading to exclusion of metabolically unhealthy women from RCTs, and other factors, may have contributed to these inconsistencies. 2. Does obesity impact AI efficacy or estrogen suppression in the adjuvant setting? Obesity is an adverse prognostic factor in women receiving letrozole or anastrozole; the relative benefit of anastrozole (but not letrozole) vs tamoxifen may be lowered in obese women. Emerging data suggest that endogenous estrogen suppression by AIs may be somewhat less complete in obese women; data are inconsistent and the clinical significance of these observations is unclear; for instance, one report suggests benefits of extended adjuvant anastrozole may be limited to normal weight women. 3. What are the potential biologic underpinnings of the obesity– breast cancer association? Components of the insulin resistance syndrome (hyperinsulinemia, dysglycemia, inflammation, altered adipokine profile) as well as obesity associated elevations in endogenous estrogen levels have been proposed as potential biologic mediators. The biology is likely complex, with the relative importance of different mediators varying across BC subtypes and over time (e.g. we found insulin to be important in the first 5 years after diagnosis while obesity and leptin associations persisted beyond 5 years). 4. Are interventions studies warranted? If so, which interventions in which populations? In the 45 years since the obesitybreast cancer prognosis association was first reported, dozens of observational studies have confirmed an adverse association, without identifying consistent subgroup patterns. It is not clear whether this association is causal, nor is it clear that reducing weight/improving metabolism will improve prognosis (ie: obesity effects may be “built into” BC biology and not be responsive to changes in weight or metabolism). The WINS RCT suggested