Breast Cancer Risk Factors

Edmund Tai, MDHematology/Oncology

PAMF

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)

Cohorts used to model

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 BRCA1/BRCA2 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

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)

Effect of calcium channel blockers and ACE inhibitors

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◦ 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)

Models used to predict BC

This model is much more accuratein 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.

Risk Factors Estimated Relative RiskAdvanced age >4Family history•Family history of ovarian cancer in women < 50y >5

•One first-degree relative >2•Two or more relatives (mother, sister) >2Personal history•Personal history 3-4•Positive BRCA1/BRCA2 mutation >4 up to 10•Breast biopsy with atypical hyperplasia 4-5

•Breast biopsy with LCIS or DCIS 8-10Reproductive 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 1.5DCIS = ductal carcinoma in situ; HRT = hormone replacement therapy; LCIS = lobular carcinoma in situ

Table 1. Risk Factors for Breast Cancer

Syndrome Gene Inheritance Cancers Other Features

Breast/ovarian BRCA1 AD Breast, ovarian

Cancer syndrome BRCA2 AD Breast, ovarian, prostate, pancreatic

Fanconi anemia in homozygotes

Li-Fraumeni syndrome TP53 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/LKB1 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 CHEK2 AD Breast Low penetrance

Muir-Torre syndrome MSH2/MLH1 AD Colorectal, breast

AD = autosomal dominant; GI = gastrointestinal.

Table 2. Genetic Breast Cancer Syndromes

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 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 1.4

Average five-year and lifetime risk of developing breast cancer among white women, by ageData from: Breast Cancer Risk Assessment Tool. National Institutes of Health.

Age

Asian women hasEarlier age of onset butScreening is not universal

Weight — Obesity (defined body mass index ≥30 kg/m2) 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/m2 had a higher breast cancer risk compared with those with a BMI <21 kg/m2 (relative risk [RR] 1.27, 95% CI 1.03-1.55) [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/m2 were 46 percent less likely to develop breast cancer than those with a BMI <21 kg/m2 [10]

There is no plausible explanation for this.

Weight and Obesity

Higher native estrogen levels is associated with increased risk in pre- and post-menopausal 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.

Estrogen exposure

 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 4-5x higher risk compare with normal breast.

No correlation between estrogen level and dense breast.

Dense Breast

This is considered a surrogate marker for exposure to estrogens.

A high bone density correlates with incidence of breast cancer

Bone mineral density

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].

Other hormone exposure