Triple-Negative Breast Cancer: Lifestyle Changes to Reduce Risk of Recurrence Serena T. Wong, MD Assistant Professor of Medicine Division of Medical Oncology The Cancer Institute of New Jersey

US breast cancer statistics Most common diagnosed cancer in women Second leading cause of cancer deaths in women (first for ages 25-60) Estimated 230, 480 new cases of invasive breast cancer in 2011 Estimated 39,520 deaths from breast cancer in 2011 1 in 8 women develop breast cancer in their lifetime

Triple-Negative Breast Cancer

Triple-Negative Breast Cancer Estrogen-receptor (ER), Progesterone-receptor (PR) and Human Epidermal Growth Factor receptor 2 (HER2) used for biological classification of breast cancers If ER-/PR-/HER2-, called Triple Negative

Patterns of Recurrence in Triple-Negative Breast Cancer Pattern (timing) of recurrence between TN and non-TN disease Triple-negative Peak recurrence at 3 yrs, declines rapidly thereafter Distant recurrence: 34% Non-Triple-negative Constant recurrence rate over time Distant recurrence: 24% Dent R et al. Clin Cancer Res 2007;13: 4429-4434

Breast Cancer Relapse is Heterogeneous Higher risk of early relapse Constant risk of relapse Anderson et al. Breast Cancer Res Treat 2006;100: 121-126

Patterns of Relapse Sites in Triple-Negative Breast Cancer Lung and brain more common compared to non-triple-negative breast cancer Bone metastases less common Dent R et al. Clin Cancer Res 2007;13: 4429-4434

Triple-Negative Breast Cancer and Chemotherapy Target not known Chemotherapy is standard Many TNBCs are exquisitely sensitive to chemotherapy Several novel agents under investigation Subset of TNBC’s are exquisitely sensitive to chemo, but unfortunately many are not

What else be done to reduce risk of recurrence?

Lifestyle Modification Can be an empowering and effective way to boost physical and mental health in breast cancer survivors Data strongly suggest that lifestyle modifications may also improve breast cancer outcomes

Lifestyle modifications Link between obesity and breast cancer outcomes Physical activity and breast cancer outcomes Diet modification Role of insulin in breast cancer? Alcohol and breast cancer Coffee intake Vitamin D

Obesity and breast cancer Obesity linked to poor outcomes in women with early stage breast cancer Meta-analysis of 43 studies examining relationship between weight at time of diagnosis and prognosis 33% increase in risk of breast cancer-related mortality and overall mortality in obese vs. non-obese women Protani et al, Breast Cancer Res Treat 2010 Chlebowski et al, JCO 2002

Obesity at time of diagnosis clearly associated with poorer outcomes Is obesity the driver or simply associated with higher risk of recurrence? Does reducing body weight after diagnosis improve outcome? Possible that tumors that develop in presence of high BMI will take on growth characteristics such that they will run the same clinical course regardless of subsequent weight variation. Or…weight loss could reduce and/or remove ongoing drivers of breast cancer growth and metastatic spread

Lifestyle modifications Link between obesity and breast cancer outcomes Physical activity and breast cancer outcomes

Physical Activity and Survival after Breast Cancer Diagnosis Prospective observational study 2987 female registered nurses in the Nurses’ Health Study who were diagnosed with stage I, II, or III breast cancer between 1984 -1998 Breast cancer mortality risk calculated according to physical activity category 2-5 years after diagnosis (<3, 3-8.9, 9-14.9, 15-23.9, or ≥24 metabolic equivalent task [MET] hours/ week) 3 MET hrs = 1 hour average paced walking 2-2.9 mph Holmes et al, JAMA 2005

Copyright © 2012 American Medical Association. All rights reserved. From: Physical Activity and Survival After Breast Cancer Diagnosis JAMA. 2005;293(20):2479-2486. doi:10.1001/jama.293.20.2479 Figure Legend: Date of download: 9/18/2012 Copyright © 2012 American Medical Association. All rights reserved.

10-yr survival rate: <3 MET: 86% ≥9 MET: 92% The 5-year survival for women who engaged in 9 or more MET-hours per week was 97%; 3 to 8.9 MET-hours per week, 97%; and less than 3 MET-hours per week, 93% (Figure). The corresponding 10-year survival rates were 92%, 89%, and 86%, respectively. The absolute unadjusted risk reduction was 4% at 5 years and 6% at 10 years for women who engaged in 9 or more MET-hours per week of physical activity compared with less than 3 MET-hours per week.

Results Protective benefit of physical activity similar among overweight and normal weight women Physical activity particularly beneficial to women with ER+ tumors (50% decrease in risk of death) But #s small in ER- group so hard to draw conclusion Physical activity beneficial in all stages, particularly in stage III

Copyright © 2012 American Medical Association. All rights reserved. From: Physical Activity and Survival After Breast Cancer Diagnosis JAMA. 2005;293(20):2479-2486. doi:10.1001/jama.293.20.2479 Date of download: 9/18/2012 Copyright © 2012 American Medical Association. All rights reserved.

Copyright © 2012 American Medical Association. All rights reserved. From: Physical Activity and Survival After Breast Cancer Diagnosis JAMA. 2005;293(20):2479-2486. doi:10.1001/jama.293.20.2479 Figure Legend: Date of download: 9/18/2012 Copyright © 2012 American Medical Association. All rights reserved.

Copyright © 2012 American Medical Association. All rights reserved. From: Physical Activity and Survival After Breast Cancer Diagnosis JAMA. 2005;293(20):2479-2486. doi:10.1001/jama.293.20.2479 Figure Legend: Date of download: 9/18/2012 Copyright © 2012 American Medical Association. All rights reserved.

Copyright © 2012 American Medical Association. All rights reserved. From: Physical Activity and Survival After Breast Cancer Diagnosis JAMA. 2005;293(20):2479-2486. doi:10.1001/jama.293.20.2479 Date of download: 9/18/2012 Copyright © 2012 American Medical Association. All rights reserved.

Postulated mechanisms? Physical activity among overweight women is associated with decrease in levels of androgen and estrogen May decrease insulin levels and improve insulin resistance (more about this later)

Lifestyle modifications Link between obesity and breast cancer outcomes Physical activity and breast cancer outcomes Diet modification

Women’s Intervention Nutrition Study (WINS) 2437 women ages 48-79 yrs with resected early stage BC Low-fat dietary intervention: -target ≤ 15% calories from fat -frequent individual counseling sessions with dietician Control group: -written info on general dietary guidelines -dietician every 3 months 2437 women assigned betwn 2/94 to 1/01 Interim analysis after median 60 months f/u Chlebowski R T et al. JNCI J Natl Cancer Inst 2006;98:1767-1776

Results Intervention group successful in lowering fat intake (33.3 g/day vs. 51.3 g/day) 6 lb lower mean body weight in intervention group compared to controls 9.8% relapse rate in intervention group vs. 12.4% in control group

CONSORT trial flow diagram. CONSORT trial flow diagram. Detailed reasons for not completing study were as follows. Not receiving intervention, intervention group: lost interest in study (n = 4), personal–family problem (n = 2), did not like low-fat eating plan (n = 1). Not receiving intervention, control group: lost interest in study (n = 2), did not like control group allocation (n = 3). Lost to follow-up, intervention group: unable to contact participant (n = 24), not interested in study (n = 3), personal–family problem (n = 2), did not like low-fat eating plan (n = 3), medical problem (n = 3), time commitment (n = 2), 5 years was enough (n = 2), moved (n = 1), refused to be contacted (n = 4), unknown (n = 1). Lost to follow-up, control group: unable to contact participant (n = 39), not interested in study (n = 5), personal–family problem (n = 2), did not like control group (n = 2), medical problem (n = 2), time commitment (n = 2), 5 years was enough (n = 2), moved (n = 2), refused to be contacted (n = 6), unknown (n = 4). Discontinued study, intervention group: unable to contact the participant (n = 49), not interested in study (n = 15), personal–family problem (n = 26), did not like low-fat eating plan (n = 21), medical problem (n = 12), time commitment (n = 10), 5 years was enough (n = 23), moved (n = 7), refused to be contacted (n = 3), unknown (n = 4). Discontinued study, control group: unable to contact the participant (n = 51), not interested in study (n = 7), personal–family problem (n = 6), did not like control group (n = 1), medical problem (n = 3), time commitment (n = 5), 5 years was enough (n = 15), moved (n = 3), refused to be contacted (n = 8), unknown (n = 7). Chlebowski R T et al. JNCI J Natl Cancer Inst 2006;98:1767-1776 © The Author 2006. Published by Oxford University Press.

24% risk reduction at median 5 yrs follow-up Kaplan–Meier estimates of relapse-free survival. Number of events/number of patients in the dietary intervention and control groups are indicated. Hazard ratio (HR) and 95% confidence interval (CI) were calculated from adjusted Cox proportional hazard model comparisons of control to dietary intervention groups through the 60-month median follow-up period. P value is two-sided. Numbers of patients at risk are indicated below the graph. Chlebowski R T et al. JNCI J Natl Cancer Inst 2006;98:1767-1776

ER+ ER- Kaplan–Meier estimates of relapse-free survival. (A) Estrogen receptor–positive subjects. (B) estrogen receptor–negative subjects. Number of events/number of patients in the dietary intervention and control groups are indicated. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated from adjusted Cox proportional hazard model comparisons of control to dietary intervention groups through the 60-month median follow-up period. P values are two-sided. Numbers of patients at risk are indicated below the graph. -stronger effect for dietary fat reduction on recurrence in women with ER- cancers; but interaction was no statistically significant and would require confirmation -predominant influence of diet on ER- cancers wouldl implicate factors other than estrogen as mediators (eg. Reduced insulin levels, reduced insulin resistance, reduced insulin-like growth factor 1, reduced inflammation markers  all may be influenced by dietary fat reduction and/or weight loss) -planned analyses of serial fasting blood samples in 2 groups will be done . Chlebowski R T et al. JNCI J Natl Cancer Inst 2006

Women's Healthy Eating and Living (WHEL) study 3088 women ages 18-70 yrs with stage I, II, or IIIA breast cancer treated within previous 4 years Intensive intervention group -target 3 svgs fruit, 5 svgs vegetables, 30 g fiber, limited fat (≤ 15-20% total calories) -telephone counseling -cooking classes -newsletters Control group -print materials describing "5-A-Day" dietary guidelines (5 svgs fruits and vegetables, >20 g fiber, <30 % total calorie intake from fat Pierce et al, JAMA 2007

Results Intervention group did achieve and maintain increased vegetable, fruit and fiber intake and decreased fat intake No difference in mean body weight between 2 groups At 7-year follow-up intensive dietary intervention did not significantly decrease either breast cancer recurrence rate (17% in both groups) or mortality (10% in both groups)

Why differing results? Intervention group in WINS study experienced weight loss of 6 lbs compared to controls No difference in weight between 2 groups in WHEL study Are the improved outcomes in WINS study a result of weight loss?

Lifestyle modifications Link between obesity and breast cancer outcomes Physical activity and breast cancer outcomes Diet modification Role of insulin in breast cancer?

Insulin Obesity leads to insulin resistance compensatory elevated levels of insulin Insulin resistance linked to breast cancer development High insulin levels associated with increased risk of breast cancer recurrence Chronically elevated insulin  increased IGF-1 levels Both growth factors that promote cell division Even modest weight loss can restore insulin sensitivity and affect action of IGF-1 Larsson et al, Int J Cancer 2007 Goodwin et al, JCO 2002

NCIC MA.32 clinical trial A Phase III Randomized Trial of Metformin vs. Placebo in Early Stage Breast Cancer To compare recurrence rates in patients with early-stage breast cancer treated with metformin vs. placebo for 5 years in addition to standard adjuvant therapy

Lifestyle modifications Link between obesity and breast cancer outcomes Physical activity and breast cancer outcomes Diet modification Role of insulin in breast cancer? Alcohol and breast cancer

Research shows connection between regular drinking and risk of developing breast cancer Nurses Health Study: ~106,000 women followed from 1980-2008 Drinking habits recorded Women who drank 3-5 drinks/wk had 15% higher risk of developing breast ca compared to nondrinkers Women who drank >30 drinks/wk had 50% higher risk Amount of alcohol more closely associated than frequency of alcohol Risks of cardiovascular disease lower among regular drinkers The Nurses' Health Study (NHS) cohort was established in 1976, when 121 700 female registered nurses aged 30 to 55 years completed a baseline questionnaire including items on risk factors for cancer and cardiovascular disease. Every 2 years, follow-up questionnaires have been sent to update risk factor information and disease development. Based on self-report, the NHS population is predominantly white (93.7% white, 2% black, 0.7% Asian, and 3.6% other or unknown race/ethnicity), reflecting the demographics of registered nurses in the United States in 1976. Follow-up has been extremely high with 4.4% of person-time lost to follow-up. We routinely search the National Death Index every 2 years for nonresponders.14 In 1976, written informed consent was not required; instead, return of completed questionnaires was considered consent to enroll in the study. The institutional review board of the Brigham and Women's Hospital reviewed and approved the study protocol. Chen et al, JAMA Nov 2011

Million Women Study 1,300,000 women in UK surveyed between 1996-2001 ~7 years follow-up Each additional alcoholic drink regularly consumed per day was associated with 11 additional breast cancers among 1000 women up to age 75 Woman who has 1 drink/d has 12% increase in relative risk compared to nondrinker 2 drinks/d 25% higher risk To determine the impact of alcohol on overall and site-specific cancer risk, Naomi Allen, D.Phil., of the University of Oxford, U.K., and colleagues examined the association of alcohol consumption and cancer incidence in the Million Women Study, which included 1,280,296 middle-aged women in the United Kingdom. Participants were recruited to the study between 1996 and 2001. Researchers identified cancer cases through the National Health Service Central Registries. Women in the study who drank alcohol consumed, on average, one drink per day, which is typical in most high-income countries such as the U.K. and the U.S. Very few drank three or more drinks per day. With an average follow-up time of more than 7 years, 68,775 women were diagnosed with cancer. The risk of any type of cancer increased with increasing alcohol consumption, as did the risk of some specific types of cancer, including cancer of the breast, rectum, and liver. Women who also smoked had an increased risk of cancers of the oral cavity and pharynx, esophagus, and larynx. The type of alcohol consumed--wine versus spirits or other types--did not alter the association between alcohol consumption and cancer risk. Each additional alcoholic drink regularly consumed per day was associated with 11 additional breast cancers per 1000 women up to age 75; one additional cancer of the oral cavity and pharynx; one additional cancer of the rectum; and an increase of 0.7 each for esophageal, laryngeal, and liver cancers. For these cancers combined, there was an excess of about 15 cancers per 1000 women per drink per day. (The background incidence for these cancers was estimated to be 118 per 1000 women in developed countries.) "Although the magnitude of the excess abso¬lute risk associated with one additional drink per day may appear small for some cancer sites, the high prevalence of moderate alco¬hol drinking among women in many populations means that the proportion of cancers attributable to alcohol is an important public health issue," the authors write. In an accompanying editorial, Michael Lauer M.D., and Paul Sorlie, Ph.D., of the National Heart, Lung, and Blood Institute, in Bethesda, M.D., emphasize that these new results derived from such a large study population should give readers pause. Although previous epidemiological studies have suggested that there is a cardiovascular benefit associated with moderate alcohol consumption, the excess cancer risk identified in the current study may outweigh that benefit. "From a standpoint of cancer risk, the message of this report could not be clearer. There is no level of alcohol consumption that can be considered safe," the editorialists write. Allen et al, JNCI Mar 2009

LACE study Almost 2000 participants with early-stage breast cancer recruited from 1997-2000 On average ~2 yrs post diagnosis Alcohol (wine, beer, liquor) intake at entry assessed by questionnaire 1 standard drink in US = 13.7 g (0.6 oz) pure ethanol Non-drinkers (≤ 0.5g/d) Occasional drinkers (0.6 – 5.0 g/d) Regular drinkers (≥ 6 g/d) Kwan, M. et al JCO 2010

Outcomes measured Recurrence Overall death Death from breast cancer Death from non-breast cancer

Results Women followed for almost 8 years Women who drank 3 or more drinks per week were 35% more likely to have recurrence compared to nondrinkers 51% more likely to die from breast cancer compared to nondrinkers Women who drank < 3 drinks/week had same recurrence risk as nondrinkers

Results Association was limited to postmenopausal women and obese women No difference seen between ER+ and ER- groups (but numbers small) Alcohol did not affect risk of death from non-breast cancer causes Etoh can possibly influence E2 metabolism and endogenous levels in pre- and post-menopausal women Obesity can elevate circulating sex hormones and insulin levels, thereby promoting E2 production and breast cell proliferation Other studies have shown that etoh can increase expression of ERs in cultured human breast cancer cells (promotes growth of ER+ but not ER- breast ca)

So how much alcohol is safe?

Lifestyle modifications Link between obesity and breast cancer outcomes Physical activity and breast cancer outcomes Diet modification Role of insulin in breast cancer? Alcohol and breast cancer Coffee intake

Swedish study Compared health histories, including coffee intake, between 2818 postmenopausal Swedish women diagnosed with breast cancer with 3,111 similar postmenopausal women without breast cancer Overall, coffee consumption associated with ~20% decrease in breast cancer risk When stratified by ER subtype, women who drank >5 cups/d were 57% less likely to be diagnosed with ER- breast cancer than women who drank ≤1 cup/d Li et al, Breast Cancer Research 2011

German Study Compared health histories of 3,464 women postmenopausal women diagnosed with breast cancer with 6,657 similar postmenopausal women not diagnosed with breast cancer Women who drank >5 cups of coffee/d were 33% less likely to be diagnosed with ER- breast cancer (but not stat signif) Li et al, Breast Cancer Research 2011

But data are conflicting Other studies have shown differing results Coffee is complex mixture Caffeine Other chemicals (eg. Phytoestrogens) Carcinogenic vs protective effects? Many different kinds of coffee – caff/decaf, instant/brewed. Polyphenols in cofee – can play dual role as both carcinogen, and chemopreventive agent w/ antioxidative and weakly estrogenic properties

Lifestyle modifications Link between obesity and breast cancer outcomes Physical activity and breast cancer outcomes Diet modification Role of insulin in breast cancer? Alcohol and breast cancer Coffee intake Vitamin D

Vitamin D Normal and malignant breast cancer cells have receptors for vit D VDR mediates cellular growth and differentiation When activated influences up to 200 genes that control cell proliferation, cell survival/death, prevention of angiogenesis

Vit D and risk of developing breast cancer Ecologic studies have shown relationship between latitude of residence and risk of BC Inverse association between vit D intake and mammographic density Low vit D levels in healthy women have been associated with increased BC mortality Information is lacking on direct prognostic effects of vitamin D in breast cancer, but low vitamin D levels in healthy women have been associated with increased breast cancer mortality (reflecting combined effects of vitamin D on breast cancer risk and prognosis).8 25-hydroxyvitamin D levels have been reported to be significantly lower in women with locally advanced or metastatic breast cancer compared with women with early-stage disease,9 whereas women diagnosed with breast cancer in northern Norway (where sun exposure is low) have poorer outcomes than women diagnosed in southern Norway (where sun exposure is greater).10 Finally, 25-hydroxyvitamin D levels shortly after diagnosis were significantly lower in American women with local versus regional breast cancer (P = .02).11 One report12 has linked high levels of 25-hydroxyvitamin D with improved mortality (hazard ratio [HR] = 0.52; 95% CI, 0.29 to 0.94) and cancer-specific mortality (HR = 0.61; 95% CI, 0.31 to 1.19) in patients with colorectal cancer.

Prognostic effects of Vit D levels in early breast cancer 512 women with early stage breast cancer in Toronto 1989-1996 Vit D level checked at time of diagnosis Deficient, insufficient or adequate Low levels associated with premenopausal status, high BMI, high insulin and high tumor grade Women who were deficient (vs adequate) had higher rate of recurrence and lower overall survival Goodwin, P et al. JCO 2009

Vit D levels and prognostic indicators Vit D levels collected from 194 early-stage breast cancer pts and 194 controls at U of Rochester 2009-2010 Breast cancer pts had lower vit D levels than controls (32.7 ng/ml vs 37.4 ng/ml) Women with suboptimal levels were 3 times more likely to have triple negative BC than women with optimal levels Those with low levels more likely to have higher Oncotype Score as well as other worse prognostic indicators Although this serum measure is a useful marker of current vitamin D exposure, associational studies have important limitations. Specifically, low serum 25-hydroxyvitamin D levels are also linked with confounding factors related to higher cancer risk, including obesity (vitamin D becomes sequestered in adipose tissue), lack of physical activity (correlated with less time outdoors and less solar exposure), dark skin pigmentation (less skin synthesis of vitamin D in response to sun), and diet or supplementation practices. Reverse-causation bias may also occur if poor health reduces participation in outdoor activities and sun exposure or adversely affects diet, resulting in lower vitamin D levels. Association therefore cannot prove causation. Many micronutrients that seemed promising in observational studies (e.g., beta carotene, vitamins C and E, folic acid, and selenium) were not found to reduce cancer risk in randomized clinical trials, and some were found to cause harm at high doses.4 The theory that vitamin D can help prevent cancer is biologically plausible. The vitamin D receptor is expressed in most tissues. Studies in cell culture and experimental models suggest that calcitriol promotes cell differentiation, inhibits cancer-cell proliferation, and exhibits antiinflammatory, proapoptotic, and antiangiogenic properties. Such findings suggest, but don't prove, that vitamin D has a role in preventing the development of cancer or slowing its progression. Peppone, L et al, Ann Surg Onc 2012

Possible explanations? Vit D regulates cell growth, differentiation and invasion of breast cancer cells Women deficient in vit D may develop higher grade tumors Vit D inhibits abnormal growth of breast cells in lab and suppresses excessive proliferation Addition of vit D to breast cancer cell cultures can reverse certain features associated with poor prognosis in human breast cancers

Recommendations Studies looking at vit D supplementation and risk of developing breast cancer have yielded conflicting results Clinical trials of vit D supplementation in women diagnosed with breast cancer needed Vit D important for other health issues (eg. bone health, arthralgias) Women should be screened for vit D deficiency and treated accordingly

Summary It is clear that both the host as well as the tumor determine cancer outcome There is a growing body of evidence that lifestyle does matter in breast cancer prognosis How lifestyle changes affect breast cancer outcomes remains unclear Possible factors linking lifestyle behaviors with breast cancer include circulating levels of estrogen, insulin, inflammatory markers, immune function

Summary Maintaining a normal BMI, regular exercise and eating a diet low in fat and high in vegetables and fruit confer beneficial effects on overall health and now seem to aid in improving breast cancer outcomes

Questions? wongse@umdnj.edu THANK YOU! Questions? wongse@umdnj.edu