Breast Cancer

Breast cancer is the second-leading cause of cancer in women (after skin cancer) and the second-leading cause of cancer-related death in women (after lung cancer), accounting for more than 40,000 deaths annually.[1] Breast cancer incidence rose through the late 20th century, but has been declining since 2002.

The incidence of breast cancer in men is about 0.8% of the rate in women. In both sexes, most cancers are invasive at the time of diagnosis; ductal carcinoma in situ (DCIS) comprises only about 20% of diagnosed breast cancers in the US. More than 85% of the invasive tumors are infiltrating ductal carcinoma. Other histologic types are infiltrating lobular, medullary, mucinous, and tubular carcinomas.

Risk Factors

Age: Less than 5% of all breast cancer diagnoses occur in women under age 40; 15% of cases occur between 40 and 50 years of age, 60% between ages 50 and 75, and 20% after age 75.[2],[3] The median age of breast cancer in the US is 62 years.

Socioeconomic status (SES): Individuals in higher SES categories (higher income, education, and skilled occupation) generally have greater risk of developing breast cancer—as high as double the incidence of the lowest SES groups. Higher SES women tend to display behaviors known to elevate risk such as having no children or fewer children, older age at first full-term birth, fewer months breastfeeding, hormone use, alcohol use, increased childhood nutrition with taller height and increased weight, and living in urban communities.[4],[5]

Race: In the US, whites have the highest breast cancer incidence of all races, with Black Americans second. However, mortality is highest in Black women.[6],[7],[8]

Genetic factors: Specific genetic mutations account for about 5-10% of breast cancer cases. These include the presence of the BRCA1, BRCA2, p53, ATM, and PTEN gene mutations.

Family history: Risk increases with an increasing number of first- or second-degree relatives with breast cancer history. Women with one affected first-degree relative have almost double the risk of developing breast cancer, compared with women without affected relatives. Risk triples for women with two affected first-degree relatives.[9]

Previous breast cancer: A first breast cancer may increase risk for subsequent contralateral breast cancer.[10]

Increased breast density: Women with mammographically “extremely dense” breast tissue, generally defined as dense tissue comprising ≥ 75 percent of the breast, have a 4-5 times increased risk of breast cancer compared with women of similar age with fatty (not dense) tissue.[11]

Proliferative benign breast disease (with or without atypia): Proliferative breast lesions without atypia (ductal hyperplasia, fibroadenoma, radial scar) can double breast cancer risk, whereas those with atypia (lobular carcinoma in situ or atypical ductal/lobular hyperplasia) can elevate risk more than 4 times.[12],[13]

Reproductive events: Early menarche, late menopause, nulliparity, lower parity, and older age at first birth are associated with higher risk.[14] In contrast, several studies show protective benefits of breastfeeding. A multinational case-control study of nearly 150,000 women showed a decreased risk of 4.3% for each year of breastfeeding and 7% for each pregnancy.[15]

Higher serum estrogen concentrations: Women with higher concentrations of circulating estrogen have a higher risk of developing breast cancer.[16] In a clinical trial with 7,705 women, those with serum estradiol concentrations in the highest tertile had twice the risk for invasive postmenopausal breast cancer compared with women with lower estradiol concentrations.[17] Circulating estrogen concentrations can be influenced by changes in fat and fiber intake, as noted in the Nutrition Considerations section.

Hormone replacement therapy (HRT): Long-term use of HRT is associated with an increased risk for breast cancer. The Women’s Health Initiative (WHI) trial showed a higher risk of breast cancer (RR = 1.26) among women taking a combined estrogen-progestin preparation for approximately 5 years, compared with those who used a placebo.[18] It has also been shown that the women who took HRT the longest were 3 times more likely to develop cancer than those who never received HRT.[19] For eligible women, unopposed estrogens may pose less risk in comparison with combination HRT, but this treatment carries other risks, such as thromboembolism.

Oral contraceptive pills: Oral contraceptives raise the risk of breast cancer slightly. Based on a 2017 study including 1.8 million women, for every 100,000 users, oral contraceptives would be expected to cause 13 extra cases of breast cancer each year.[20] This added risk diminishes rapidly after use is discontinued. It is noteworthy that that oral contraceptives reduce the risk for cancer of the ovary, endometrium, and colorectum.[21]

Physical inactivity: Physically inactive women are more likely to develop breast cancer, compared with active women. Exercise may decrease risk by reducing circulating estrogen and androgen concentrations and increasing sex-hormone binding globulin concentrations.[22] In the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial involving nearly 39,000 women, roughly 4 hours per week of exercise was associated with a > 20% reduction in breast cancer risk, compared with women reporting no physical exercise.[23] Some evidence indicates that exercise may reduce risk regardless of hormone receptor subtype (i.e., ER+/PR+ or ER-/PR-) or menopausal status.[24]

Other factors: Most studies have shown no increased risk from underwire bras, deodorant or antiperspirant use, cell phones, microwaves, abortion, infertility drugs, silicone breast implants, electromagnetic fields, electric blankets, hair dyes, or organochlorines.[25],[26]

Screening

Mammography remains the primary method for breast cancer screening in average-risk women. Other methods, such as magnetic resonance imaging, tomosynthesis, and ultrasound serve as adjuncts for higher-risk individuals. Breast self-examination and clinical breast examinations are no longer recommended for routine screening.

Published screening guidelines vary in their recommendations, particularly with regard to the age for starting screening mammography for average risk women (ranging from 40 to 50) and on the frequency of screening (1 to 2 years).[27] ,[28] ,[29] ,[30] ,[31] Mammography reduces breast cancer mortality in women aged 50-69, but also carries the risk of overdiagnosis—the detection of clinically insignificant, non-life-threatening cancers.[32] For women aged 40-49, the benefits of mammography are not yet clear.[33]

Screening decisions should take into consideration overall breast cancer risk and individual preferences. Women at higher risk may benefit from more frequent screening at an early earlier age.

Diagnosis

Presenting signs and symptoms of breast cancer may include a palpable breast mass (most common), dimpling, pain, nipple inversion or unilateral nipple discharge (especially when bloody or watery), peau d’orange (“orange peel skin”), erythema, or other skin changes.

All palpable breast lumps should be evaluated thoroughly with diagnostic mammography, ultrasound, and/or fine-needle aspiration biopsy (FNAB) or core needle biopsy (CNB) to determine whether the lump is a simple cyst or a complex/solid mass. An FNAB with bloody aspirate must be cytologically evaluated.

A suspicious mass on mammogram requires tissue sampling, and a mass not clearly benign requires magnified or spot compression mammography in addition to possible ultrasound. Complex cysts or solid masses on ultrasound need FNAB, CNB, or excisional biopsy for definitive evaluation.

Treatment

Most patients who are diagnosed with invasive breast cancer have early stages I and II (82%), some have locally advanced stage III breast cancer (13%), and a small percentage (5%) present with stage IV distant metastatic disease.[34] This determination is based on the TNM staging system: primary tumor size, regional lymph node involvement, and presence of distant metastasis. Other factors that will affect the prognosis and preferred treatment of breast cancer include menopausal status, age, biologic factors (grade, hormone receptor status, and HER2) and genomic profiles (e.g., Oncotype, MammaPrint).

Surgery, radiation, chemotherapy, hormone therapy, and biologic targeted drug therapies (e.g., trastuzumab) are involved in the primary treatment of breast cancer, depending on the stage and intrinsic cancer biology. Many possible algorithms have been developed, and each patient’s presentation should be evaluated to determine the best treatment.

In early-stage cancer, breast-conserving procedures, such as lumpectomy or segmental mastectomy followed by radiation, have been shown to be as effective as mastectomy, with statistically similar rates of both overall survival and locoregional recurrence.[35]

Evaluation of the axillary lymph nodes is also important for staging. This can involve the preoperative biopsy of clinically suspicious lymph nodes with subsequent axillary node dissection if positive. In the absence of clinically suspicious lymph nodes, a sentinel lymph node biopsy during breast surgery can be obtained. When axillary nodes are positive, adjuvant treatment with endocrine therapy, chemotherapy, and/or biologic therapy is generally recommended.

Invasive disease with nodal metastases or with triple-negative or HER2-positive tumor profiles usually requires neoadjuvant systemic therapy, which is designed to shrink the tumor prior to surgery. These patients also typically receive adjuvant treatment such as radiation or hormonal therapy.

Tumor characteristics predict which patients are likely to benefit from specific types of therapy. Tumors that are positive for the HER2 receptor should receive a HER2-directed agent, such trastuzumab. Women with estrogen-receptor-positive or progesterone-receptor-positive cancers benefit from hormonal therapy, such as tamoxifen and/or aromatase inhibitors such as exemestane or anastrozole. Conversely, women who are receptor-negative may benefit from adjuvant chemotherapy, particularly if they are under 50 years or premenopausal. Hormonal therapy or chemotherapy is often used in the treatment of recurrent or systemic disease. Genetic tests may also help identify those who are most likely to benefit from certain treatments.

Nutritional Considerations

Nutritional factors may reduce both the risk of developing cancer and the likelihood of cancer progression and mortality after diagnosis. Both are discussed below.

Nutrition and Risk Reduction

Western diets high in meat, high-fat dairy products, fat (particularly saturated and omega-6 fatty acids), processed foods, and simple sugars, while simultaneously low in fruits, vegetables, legumes, whole grains, and fiber are linked to higher breast cancer risk.[36],[37] Breast cancer is less prevalent in countries where simple plant-based foods are staples.[38],[39],[40] Incidence increases successively in first- and second-generation immigrants to North America in proportion to the degree to which they adopt a Western diet and lifestyle.[41],[42],[43]

This risk may be explained in part by the increase in estrogen activity resulting from the conversion of androgens to estrogens in adipose tissue and the increase in circulating estrogens resulting from a fatty, low-fiber diet.[44],[45] In controlled studies, high-fiber, low-fat diets have been shown to significantly estradiol, estrone, and testosterone concentrations.[46],[47],[48],[49]

Dietary factors may also influence the age of menarche, which can also increase lifetime estrogen exposure.[50]

Animal fat and animal protein intake are linked to elevated levels of insulin-like growth factor-1 (IGF-1).[51] As a potent growth promoter, IGF-1 may be associated with other established risk factors for breast cancer (e.g., breast density), and women with high circulating levels of IGF-1 have 38% more estrogen-driven breast cancers than those with low IGF-1.[52],[53]

Specific dietary factors and dietary patterns under investigation for a potentially helpful role are described below.[54],[55]

Healthy body weight: The relationship between weight and breast cancer risk varies with menopausal status. In premenopausal women, an elevated body mass index (BMI) is associated with a lower risk of breast cancer. The reason for this is unclear.[56],[57] The opposite is true for postmenopausal women. An elevated BMI is associated with a significantly higher risk of breast cancer.[58],[59],[60] Elevated estrogen levels, presumably due to peripheral aromatization of androstenedione to estrone (and, to a lesser extent, testosterone to estradiol) in adipose tissue, may help explain this increased risk.[61]

Avoiding alcohol: Alcohol consumption increases breast cancer risk.[62] For premenopausal women, each glass of wine consumed per day increases the chances of developing breast cancer by about 7%. Two glasses a day increase a woman’s risk by 14%, and so on. The same is true for other alcoholic beverages. A bottle of beer, a 5-ounce glass of wine, and a shot of liquor all have about the same alcohol content. For older women, the effect is amplified. For each drink a postmenopausal woman consumes daily, her risk of breast cancer increases by about 13%.56 Another meta-analysis found that relative to nondrinkers and occasional drinkers, heavy drinkers had a 61% higher risk of breast cancer.[63]

Limiting or avoiding meat. A number of studies, including the Nurses’ Health Study II and the UK Women’s Cohort Study, have found significant associations between meat intake and breast cancer risk, with a 64% greater risk for postmenopausal breast cancer when women who consumed processed meat (bacon, sausage, ham, deli meats) were compared with those who did not.[64][64],[65]The NIH-AARP study involving nearly 200,000 women found a 25% higher risk for breast cancer in those eating the most red meat, compared to those eating the least.[66] When all published studies, which vary in quality, are combined in meta-analyses, results have been less straightforward.[67],[68],[69],[70]

Minimizing meat intake appears to be especially important for teens, as mammary cells develop and divide rapidly during adolescence. A study of the Nurses’ Health Study II cohort found that women who ate the most red meat in adolescence had a 42% higher risk of premenopausal, although not postmenopausal, breast cancer later in life, relative to those who ate the least meat.[71]

It is not yet clear whether these associations reflect the effect of meat-based diets on hormone concentrations, the presence of carcinogens (e.g., heterocyclic amines, polycyclic aromatic hydrocarbons), or other factors. Conversely, plant-derived foods appear to reduce breast cancer risk (see below).

Emphasizing vegetables and legumes. Vegetables have bioactive components, including folate and carotenoids, which may confer protection against breast cancer. Folate may be especially important in women who consume alcohol.[72] Foods that contain folate (leafy green vegetables, legumes, oranges) have been found more effective than folic acid supplements, perhaps due to the presence of other protective factors (e.g., fiber, vitamin C, and phytochemicals). The European Prospective Investigation into Cancer and Nutrition (EPIC) study concluded that higher vegetable intakes were related to a 13% lower breast cancer risk compared with the lowest level of consumption, an effect that was more demonstrable for ER-/PR- cancers than ER+/PR+ ones.[73] These effects may be due to vegetables high in carotenoids, higher concentrations of which were associated in the Nurses’ Health Study with 18-28% lower risk of breast cancer and inversely associated with breast cancer recurrence and mortality from this disease, over a follow-up period of 20 years.[74]

Consumption of legumes, particularly soy products, that are high in isoflavones and lignans is also associated with lower risk for breast cancer, an effect that is greater if soy foods are consumed in abundance during adolescence.[75] A meta-analysis of soy intake and breast cancer risk found a roughly 35% lower risk for ER+/PR+ cancers and a roughly 40% lower risk for ER-/PR- types, as well as significant decreases in breast cancer recurrence and mortality in high versus low soy consumers. These effects have been attributed in part to inhibition of vascular endothelial growth factor (VEGF), pro-apoptotic effects, inhibition of tyrosine kinase, induction of tumor suppressor proteins, and down-regulation of HER2, among other mechanisms.[76] These findings are particularly important, giving the popular myth that soy products may increase breast cancer risk; evidence strongly suggests a significant preventive effect.

Further evidence of the benefits of legumes was noted in the Nurses’ Health Study II, in which eating beans or lentils twice per week was associated with a 24% lower risk, compared with consuming those foods less than once per month.[77] Higher intakes of plant protein and nuts during adolescence have also been associated with significantly lower breast cancer risk during adulthood when compared with lower intakes.[78]

Reducing fat. Many studies have examined the effect of fat intake on breast cancer risk. The greatest risk appears to come from saturated fat and animal fat.[79],[80],[81],[82] Vegetable oils, such as olive oil, have not been shown to increase breast cancer risk.[83],[84],[85],[86] However, high-fat diets in general (not just saturated fat) may promote weight gain, and this weight gain elevates postmenopausal breast cancer risk, as noted above.[87]

The Women’s Health Initiative Dietary Modification Trial, including 48,835 women who were cancer-free at baseline, tested a diet that aimed to reduce fat intake to 20% of energy and to increase vegetable and fruit consumption. Participants were consuming more fat than the US average at study baseline. The actual fat intake achieved by study participants averaged 24% of energy at 1 year and drifted upward toward baseline values by the intervention’s end after a median of 8.5 years. Even so, after 17.7 years of follow-up, deaths after breast cancer were 15% lower in the dietary intervention group.[88]

Increasing fiber. Dietary fiber intake is inversely associated with the risk for breast cancer.[89] Dietary fiber interrupts the enterohepatic circulation of estrogen by binding unconjugated estrogens in the gastrointestinal tract.[90] High-fiber, low-fat diets reduce serum estradiol, which is known to be associated with breast cancer risk.[91] Fiber is abundant in plants and absent from animal products.

High-fiber diets help keep blood glucose levels within normal limits and lower the risk for adult-onset diabetes, both of which have been related to increased breast cancer risk.[92]

Managing blood glucose: Elevated fasting glucose levels are associated with breast cancer risk in nondiabetic women.[41],[93] Postmenopausal women with diabetes have been shown to have a slightly greater risk for breast cancer, compared with those who did not have diabetes.[94] As discussed in the Diabetes Mellitus section, fat build-up in muscle and liver cells contributes to insulin resistance and to the risk of diabetes.

Vitamin D adequacy: In a pooled analysis of 2 studies examining vitamin D and risk of breast cancer, women whose serum 25(OH)D levels were in the lowest quintile (< 13 ng/dL) had twice the odds of developing breast cancer as those whose levels were in the highest quintile (> 52 ng/dL). An inverse dose-response relationship was detected, suggesting that the lower the circulating vitamin D level, the higher the risk of breast cancer.[95] The authors reported that a level of 50 ng/dL could be achieved by oral intake of 2,000 IU of vitamin D3, coupled with moderate, regular sun exposure.

Nutrition and Breast Cancer Survival

The following are under investigation for their potential for reducing breast cancer recurrence and improving survival after diagnosis:

Lower body weight. Breast cancer patients with a BMI ≥ 30 kg/m2 have increased morbidity and mortality and gaining more than 5 percent of initial weight during or after treatment—irrespective of baseline BMI—increases the risk of recurrence and reduces survival fivefold.[96],[97]

An overweight initial body weight or weight gain after a diagnosis of breast cancer is associated with higher all-cause mortality in breast cancer patients.[98],[99] In one systematic review and meta-analysis, a weight gain of 10% or more of baseline weight was associated with a nearly 25% greater risk for mortality, although the association was not significant for women who were diagnosed at a healthy weight (i.e., BMI < 25 kg/m2).[98] A previous meta-analysis found that having a BMI >30 kg/m2 was associated with a roughly 40% greater overall mortality risk; for breast cancer-specific mortality, the risk was 75% higher for premenopausal women and 34% higher for postmenopausal women, compared with normal weight women.[99]

Lower-fat diets. A meta-analysis of studies involving nearly 10,000 women found a 23% lower risk for breast cancer recurrence and a 17% lower risk for breast cancer mortality in women consuming low-fat diets.[100] With regard to specific fat subtypes, most studies found that saturated fat intake prior to diagnosis was associated with increased risk of breast cancer-specific and all-cause mortality, while trans fat intake after diagnosis was associated with a 45% and 78% increased risk of breast cancer specific and all-cause mortality, respectively.[101],[102]

Breast cancer patients in the highest tertile of butter, margarine, or lard consumption have a 67% higher cancer recurrence, and a 212% higher mortality, relative to the lowest third.[103],[104]

A Seattle research center followed more than 4,400 breast cancer patients who had not yet had a recurrence and found that 3% died within 7 years.[105] Women who consumed the most trans fat had a 78% higher risk of all-cause mortality, while those consuming the most saturated fat had a 41% increased risk of all-cause mortality relative to those consuming the least. Saturated fats are solid at room temperature and come predominantly from animal sources like cheese, milk, butter, cream, meat, and eggs, although tropical oils (e.g., palm, palm kernel, coconut) are also high in saturated fat. Trans fats are commonly found in baked goods like cakes and cookies, fried foods, margarine, and shortening, as well as in some animal products.[106]

Avoiding high-fat dairy products. In the Life After Cancer Epidemiology (LACE) Study, breast cancer patients eating 1 or more daily servings of high-fat dairy products daily had a 49% increased risk of all-cause mortality compared with those consuming less than a half-serving per day.[107]

Higher intake of soy-containing foods. Women previously diagnosed with breast cancer who then consume higher amounts of soy-based foods have significantly lower risk for both disease recurrence and mortality.[108]

Fruits and vegetables. A secondary analysis of 3,080 breast cancer survivors enrolled in the Women’s Healthy Eating and Living (WHEL) study found a 30% reduction in mortality risk in women consuming the most vegetables compared to those eating the fewest. In women taking tamoxifen, the mortality risk was roughly 45% lower in the high vegetable group, and mortality risk was lowest (~ 50% reduction) in women who consumed higher amounts of cruciferous vegetables in addition to taking tamoxifen.[109]

Certain fatty acids and micronutrients, including vitamins C and D, and folate, may be important in moderating mortality risk in breast cancer patients. Higher intakes of long-chain omega-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) fatty acids were associated with a 25% reduction in breast cancer recurrence and improved overall mortality in a study of more than 3,000 women with early stage breast cancer followed for a median of 7 years.[110]

A meta-analysis of prospective studies involving nearly 18,000 women found that both dietary and supplementary vitamin C intake were significantly associated with lower total and breast cancer-specific mortality.[111] In a meta-analysis of prospective studies including roughly 7,300 women, those with the highest versus lowest dietary folate intake had a 26% lower risk of all-cause mortality; a 21% lower risk of breast-cancer specific mortality was also seen in those with the highest dietary folate, but did not reach statistical significance.[112] Meta-analyses of the association between vitamin D and breast cancer survival have reported that higher concentrations of 25(OH)D were associated with improved survival.[113]

Orders

To reduce risk of developing cancer or to improve survival post-diagnosis, the following steps are indicated:

1. Low-fat vegan diet, emphasizing vegetables, fruits, and soy products.

2. Regular physical activity consisting of 5 hours per week of moderate workouts or 2.5 hours per week vigorous workouts.

3. Aim to maintain ideal body weight, using the diet and activity steps above.

4. Avoid alcohol.

5. Avoid tobacco and second-hand smoke.

6. During active treatment, have dietary orders written in collaboration between the treating physician and a consulting dietitian.

What to Tell the Family

The families of breast cancer patients can help the patient undergoing treatment and in making diet and lifestyle changes that optimize health. Also, because breast cancer sometimes runs in families, it is important for family members to reduce their risk to the extent possible through the diet and lifestyle changes and have regular screening.

Genetic counseling should be considered for family members of patients diagnosed with breast cancer who carry an inherited mutation, such as the BRCA1 or BRCA2 genes, or who are otherwise at high risk for hereditary breast cancer.

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