Breast Cancer Risk Factors Edmund Tai MD HematologyOncology

Breast Cancer Risk Factors Edmund Tai, MD Hematology/Oncology PAMF

Cohorts used to model � American Cancer Society Cancer Prevention Study-II � Harvard Nurses' Health Study (NHS) � Hawaii-Los Angeles Multiethnic Cohort � Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial � European Prospective Investigation into Cancer and Nutrition (EPIC)

Factors that increase the risk of breast cancer include the following: • Advanced age • Family history of cancer in a first-degree relative – Family history of ovarian cancer at < 50 years, 1 first-degree relative with breast cancer, ≥ 2 first-degree-relatives with breast cancer • Personal history – Positive BRCA 1/BRCA 2 mutation, breast biopsy with atypical hyperplasia, breast biopsy with lobular or ductal carcinoma in situ • Reproductive history – Early menarche (< 12 years), late menopause, late age of first term pregnancy (>30 years) or nulliparity • Use of estrogen-progesterone hormone replacement therapy (HRT) • Current or recent oral contraceptive use • Lifestyle factors – Adult weight gain, sedentary lifestyle, alcohol consumption

Effect of calcium channel blockers and ACE inhibitors Essential update: Calcium-channel blockers associated with increased breast cancer risk and ACEIs with reduced risk � A population-based observational study of 880 women with invasive ductal breast carcinoma (IDC), 1027 with invasive lobular breast carcinoma (ILC), and 856 without cancer determined that long-term (≥ 10 years) use of calcium-channel blockers was associated with a more than doubled risk of developing either type of cancer. [1, 2, 3] � In this study, the odds ratio (OR) was 2. 4 for developing IDC (95% confidence interval [CI], 1. 2 -4. 9) and 2. 6 for developing ILC (95% CI, 1. 3 -5. 3). [2] Long-term use of angiotensin-converting enzyme (ACE) inhibitors was associated with a reduced risk for both IDC (OR, 0. 7) and ILC (OR, 0. 6) �

Models used to predict BC � BRCA probability tools include the following: BRCAPRO model Myriad I and II Manchester Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) ◦ Ontario Family History Assessment Tool (FHAT) ◦ ◦ � Breast cancer risk prediction tools include the following: ◦ Gail model 2 (used as the basis for eligibility for a number of the breast cancer prevention trials) ◦ Women’s Contraceptive and Reproductive Experiences (CARE) model (developed to address concerns regarding applicability of the Gail model to black women)

This model is much more accurate in predicting outcome than stage.

Soy and breast cancer � There is no clear evidence that when taken as part of a normal diet in reasonable amounts that soy would cause breast cancer. � In patients who has breast ca there is no evidence that soy increases relapse risk despite it weak estrogenic effect. The biology of the cancer probably dictates relapse risk to a much higher degree than the amount of soy intake. � Avoid supplement of soy, prefer natural foods like edamame, tofu, etc.

Table 1. Risk Factors for Breast Cancer Risk Factors Estimated Relative Risk Advanced age >4 Family history • Family history of ovarian cancer in women < 50 y >5 • One first-degree relative >2 • Two or more relatives (mother, sister) >2 Personal history • Personal history 3 -4 • Positive BRCA 1/BRCA 2 mutation >4 up to 10 • Breast biopsy with atypical hyperplasia 4 -5 • Breast biopsy with LCIS or DCIS 8 -10 Reproductive history • Early age at menarche (< 12 y) 2 • Late age of menopause 1. 5 -2 • Late age of first term pregnancy (>30 y)/nulliparity 2 Use of combined estrogen/progesterone HRT 1. 5 -2 Current or recent use of oral contraceptives 1. 25 Lifestyle factors • Adult weight gain 1. 5 -2 • Sedentary lifestyle 1. 3 -1. 5 • Alcohol consumption 1. 5 DCIS = ductal carcinoma in situ; HRT = hormone replacement therapy; LCIS = lobular carcinoma in situ

Table 2. Genetic Breast Cancer Syndromes Syndrome Gene Inheritance Cancers Breast/ovarian BRCA 1 AD Breast, ovarian Cancer syndrome BRCA 2 AD Breast, ovarian, prostate, pancreatic Li-Fraumeni syndrome TP 53 AD Breast, brain, soft-tissue sarcomas, leukemia, adrenocortical, others Cowden disease PTEN AD Breast, ovary, follicular thyroid, colon Adenomas of thyroid, fibroids, GI polyps Peutz-Jeghers syndrome STKII/LKB 1 AD GI, breast Hamartomas of bowel, pigmentation of buccal mucosa Ataxia-telangiectasia ATM AD Breast Homozygotes: leukemia, lymphoma, cerebella ataxia, immune deficiency, telangiectasias Site-specific CHEK 2 AD Breast Low penetrance Muir-Torre syndrome MSH 2/MLH 1 AD Colorectal, breast AD = autosomal dominant; GI = gastrointestinal. Other Features Fanconi anemia in homozygotes

Age-risk increases with age � Birth to age 39 – 0. 49 (1 in 203 women) � Age 40 to 59 – 3. 76 (1 in 27 women) � Age 60 to 69 – 3. 53 (1 in 28 women) � Age 70 and older – 6. 58 (1 in 15 women) � Birth to death – 12. 29 (1 in 8 women) Data from SEER between 2006 -2008

Age Average five-year and lifetime risk of developing breast cancer among white women, by age Data from: Breast Cancer Risk Assessment Tool. National Institutes of Health. Age Five-year risk, percent Lifetime (until age 90) risk, percent 35 0. 3 12. 6 40 0. 6 12. 4 50 1. 3 11. 2 60 1. 8 9. 1 70 2. 2 6. 3 80 2. 0 3. 1 85 1. 4

Asian women has Earlier age of onset but Screening is not universal

Weight and obesity � � � Weight — Obesity (defined body mass index ≥ 30 kg/m 2) is associated with an overall increase in morbidity and mortality. However, the risk of breast cancer associated with BMI appears to depend on the menopausal status of women. Postmenopausal women — A higher body mass index (BMI) and/or perimenopausal weight gain have been consistently associated with a higher risk of breast cancer among postmenopausal women [10 -16]. As examples: ●In a 2000 analysis of seven cohort studies, women with a BMI >33 kg/m 2 had a higher breast cancer risk compared with those with a BMI <21 kg/m 2 (relative risk [RR] 1. 27, 95% CI 1. 031. 55) [10]. ●In the Nurses' Health Study, women who gained 10 kg or more since menopause had a higher risk of breast cancer compared with women who maintained their weight (400 versus 339 per 100, 000 person-years; RR 1. 18, 95% VI 1. 03 -1. 35) [12]. These are considered a low impact risk factor.

Weight and Obesity � Premenopausal women — Unlike postmenopausal women, an increased BMI is associated with a lower risk of breast cancer in premenopausal women [10, 19]. In the 2000 pooled analysis discussed above, premenopausal women with a BMI ≥ 31 kg/m 2 were 46 percent less likely to develop breast cancer than those with a BMI <21 kg/m 2 [10] � There is no plausible explanation for this.

Estrogen exposure � Higher native estrogen levels is associated with increased risk in pre- and postmenopausal women � The level of estradiol and estrone correlates with increased risk of BC � Premenopausal women-The limited data suggest that estrogen levels also play a role in the development of breast cancer among premenopausal women with the highest quartile has a RR 2. 4 compare with the lowest quartile.

Dense Breast � The density of breast tissue reflects the relative amount of glandular and connective tissue (parenchyma) to adipose tissue(dense tissue comprising ≥ 75 percent of the breast). � Age and frequency of dense breast ◦ age 30 -70% ◦ age 50 -50% ◦ age 70 -30% � Breast density does not lead to increased mortality from BC � Dense breast is 4 -5 x higher risk compare with normal breast. � No correlation between estrogen level and dense breast.

Bone mineral density � This is considered a surrogate marker for exposure to estrogens. � A high bone density correlates with incidence of breast cancer

Other hormone exposure Androgens — Elevated androgen (ie, testosterone) levels have been associated with an increased risk of postmenopausal and premenopausal breast � Insulin pathway and related hormones — Although diabetes is not considered a breast cancer risk a large pooled analysis drawing from 17 prospective studies suggested that insulin growth factor-1 was associated with breast cancer risk in both premenopausal and postmenopausal women � � In addition, the Women’s Health Initiative reported that higher endogenous insulin levels were associated with an increased risk of breast cancer among nondiabetic, postmenopausal women who did not take menopausal hormone therapy (HR for highest versus lowest quartile of insulin level 2. 40, 95% CI 1. 30 -4. 41)

Other hormone exposure In utero exposure to diethylstilbestrol — Before 1971, several million women were exposed in utero to diethylstilbestrol (DES) that was given to their mothers to prevent pregnancy complications. Whether these women are also at an increased risk for breast cancer is unclear: � ●A long-term follow-up study of 4653 DES-exposed women and 1927 unexposed controls reported a nearly twofold increase in the cumulative risk of breast cancer in exposed women aged 40 or older (3. 9 versus 2. 2 percent, HR 1. 82, 95% CI 1. 04 -3. 08) [61]. � ●However, in a long-term follow-up study of 12, 091 DES exposed women in the Netherlands, there was no excess risk for breast cancer when compared with Dutch population-based controls, even when the analysis was restricted to women over the age of 40 (standardized incidence ratio [SIR] 1. 09, 95% CI 0. 91 -1. 31) [62]. �