Optimizing breast health

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Table 1

Managing breast problems in the current medical-legal climate can be a particularly harrowing task, especially when considering that nearly 60% of breast cancer-related litigation stems from a delay in diagnosis.¹ Complicating matters is the lack of consensus on when to start screening mammograms given varying recommendations by the United States Preventive Services Task Force (USPSTF), the American Cancer Society, the American Society of Breast Surgeons, and the American College of Obstetricians and Gynecologists (ACOG). And while these organizations generally agree on screening women aged 50 to 74, there is debate regarding screening of older women, including if, and when, to stop such screening. 

Additional confusion arises from the precise role of risk factor assessment in screening paradigms. Identification of high-risk patients allows for more focused surveillance strategies. Moreover, because primary prevention of cancer is far preferable to early detection, risk factor reduction strategies represent a major lost public health opportunity. With implementation of extended genetic testing, we are finding more women who are at higher risk for developing breast cancer over the course of their lifetime, expanding the role of primary breast providers. But confusion frequently exists over which women warrant genetic testing. Moreover, identification of at-risk women begs the question of which imaging modality to use and how often to surveil them. Finally, management of benign breast lesions can be anxiety-provoking for both a patient and her ob/gyn. In this editorial we attempt to provide a simplified yet evidence-based approach to these breast care conundrums.

When to start and stop routine screening
The average 40-year-old woman has a 1.5% risk of developing breast cancer by age 50 and incidence of false-positive results from an initial mammogram is near 15%. However, in women diagnosed with breast cancer in their 40s, there is a 20% improvement in overall 5-year survival (97%; 95% CI 92-99% vs 77%; 95% CI 69-85%) among those detected on screening mammogram vs. other means of diagnosis, and a 23% increase in disease-free 5-year survival (94%; 95% CI: 87-97% vs 71%; 95% CI: 62-78%).²In addition, there is about a 1-cm decrease in tumor size, and greater than 50% reduction in lymph node positivity when tumors are found on screening mammography.² In addition, affected women younger than age 50 have a higher incidence of estrogen receptor (ER)-negative and triple-negative (i.e., ER, progesterone receptor [PR] and human epidermal growth factor receptor-2 [HER2]-negative) tumors, which portend a worse prognosis.³ For all these reasons, it is our practice to recommend annual screening mammograms beginning at age 40 through age 50. 

There is greater consensus among relevant societies and organizations that average-risk women aged 50 to 74 should have biennial screening. But screening beyond age 74 must balance detection with complication rates. While 26% of breast cancer deaths annually occur in women older than age 74, randomized trials are lacking on the utility of screening mammography in this age group.⁴ Because breast cancer incidence peaks in the late 70s, we recommend continued screening in this population until a patient has a less than 10-year expected survival. Our rationale is that the survival benefit accruing mammography is seen over a 10-year interval, thus women with a less than 10-year life expectancy are unlikely to experience a survival advantage with continued screening.⁴

After this point, an annual discussion should be had with patients regarding the risks and benefits of continued screening. About 2 out of 1,000 women screened every other year from age 70 to 79 will avoid breast cancer death. However, this benefit must be balanced against a 12% to 27% false-positive mammogram rate with 10% to 20% of these women undergoing biopsies. Another consideration is that 30% of screen-detected cancers in this age group would not otherwise present clinically yet virtually all older women diagnosed with breast cancer undergo treatment and treatment-related morbidity increasing with age.⁵

Risk factor identification and mitigation strategies
Risk factors associated with breast cancer include age, reproductive characteristics, lifestyle factors, radiation exposure to the chest wall, family history and genetics. Incidence of breast cancer increases with age, with peak incidence, as noted, occurring in the mid to late 70s. Moreover, 70% of breast cancer deaths occur in women over 60.⁶ Reproductive risk factors are linked to increased lifelong exposure to estrogens and include early menarche, late menopause, delayed first pregnancy and low parity.⁶ For every 1-year delay in menopause, breast cancer risks increase by 3%; alternatively, each 1-year delay in menarche and additional birth decreases risks by 5% and 10%, respectively.⁷ Dense breasts represent another reproductive tract risk factor, with individuals in the highest density category having a relative risk (RR) of 6.05 (95%CI: 2.82-12.97) compared with those in no density category.⁸

While these reproductive risk factors are generally not modifiable, exposure to exogenous estrogens and progestins are also associated with increased risk, particularly in the perimenopausal and early menopausal period. The RR of breast cancer among current users of estrogen and progestin menopausal hormone therapy is greater if such treatment was begun before or soon after menopause compared with more than 5 years after its onset (RR of 1.53; 95% CI:1.38-1.70 vs. 2.04; 95% CI: 1.95-2.14, respectively).⁹ For estrogen-only hormone therapy, breast cancer risks were only observed with current use in the perimenopausal period to 5 years after menopause (RR of 1.43; 95% CI: 1.35-1.51) but not when therapy is begun 5 years or more after menopause.⁹ This increased risk of breast cancer is decreased 2 years after hormone cessation. 

Similarly, women using hormonal contraceptives have an adjusted (adj) RR of breast cancer of 1.2 (95%CI: 1.14-1.26) compared with “never users”.¹⁰ Moreover, risk of breast cancer increases with duration of exposure with an adjRR of 1.46 (95%CI: 1.32-1.61) associated with oral contraceptive use for more than 10 years. This risk decreases after cessation of therapy with a residual risk of 1.08 (95%CI: 0.97-1.20) 10 years after stopping hormonal contraception. Thus, use of exogenous estrogens and progestins should be minimized in high-risk women.

Lifestyle choices such as a sedentary lifestyle, cigarette smoking, excessive alcohol use and high dietary fat intake are also associated with increased breast cancer risk and present clear prevention targets. Women who consume 30 g/day of alcohol have an increased risk of both ER+ and ER- breast cancers compared to never users (pooled multivariable RR of 1.35; 95%CI: 1.23-1.48, and 1.28; 95%CI: 1.10-1.49, respectively).¹¹ Overweight and obese postmenopausal women have increased rates of invasive breast cancer compared to women with normal weight.¹² The higher the body mass index (BMI), the greater the risk, with grade 2 and 3 obesity linked to more advanced disease, positive lymph nodes, and metastasis as well as death from breast cancer (Hazzard Ratio of 2.11; 95% CI, 1.57-2.84). Multiple studies suggest a diet lower in fats with a greater proportion of “healthy” fats reduces risk of death from all causes in breast cancer survivors.¹³ Smoking, especially when started at an early age, and in association with alcohol use, has also been associated with an increased risk of breast cancer.⁶

Women who received mantle radiation between ages 10 and 30 have up to a 15% risk of breast cancer by age 40 and starting screening mammograms early in them is recommended.¹⁴ Among female childhood cancer survivors treated with chest irradiation, cumulative incidence of breast cancer by age 50 is 30% (95% CI: 25-34%), and among Hodgkin lymphoma survivors, incidence is 35% (95% CI: 29-40).¹⁵ All such patients should be entered into a high-risk screening program as outlined below and should start 8 years after their radiation exposure or at age 25, whichever is later.¹⁵

Genetic risks 
Almost 25% of women with breast cancer have a family history of the disease, and women with an affected first-degree relative have a 1.75-fold higher risk of developing cancer.⁶ That risk increases to 2.5-fold with two or more affected first-degree relatives. Multiple genes have been identified that are associated with breast cancer. While BRCA1and BRCA2have received much attention as they are linked to 20% to 25% of hereditary breast cancers and 5% to 10% of all breast cancers, 6 genetic testing has expanded to include 28 genes. Table 1 presents the National Comprehensive Cancer Network (NCCN) guidelines for genetic testing. Genetic counselors can be a good referral source, should there be a need for genetic testing. If no genetic counselor is available in your area, then referral to a breast surgeon is appropriate to discuss family history as well as a patient’s lifetime risk of breast cancer and need for genetic testing.

Management of high-risk patients
Identifying women who have a high lifetime breast cancer risk is best done with a risk ascertainment tool. We prefer the Tyrer-Cuzick model, available online through the International Breast Cancer Intervention Study (http://ibis.ikonopedia.com/), combined with genetic testing as indicated.¹⁶ High-risk screening is now common for women with an estimated lifetime breast cancer risk of 20% or greater, including women with a known genetic mutation. Radiologists typically recommend that these women undergo alternating mammogram and magnetic resonance imaging (MRI) studies every 6 months. In women with a family history of breast cancer in at least one first-degree relative, screening imaging is recommended 10 years earlier than the youngest affected woman, but not before age 30.¹⁴ Adding MRI screenings as an adjunct to yearly mammograms has shown some long-term improvement in survival, and the average tumor size at detection is smaller than in women who undergo annual mammography alone.¹⁷

Use of ultrasound in addition to screening with mammograms and MRI is not routinely recommended but may be appropriate at the time of mammography in women with very dense breasts, or when concern exists about a focal lesion on mammogram.¹⁴ Molecular breast imaging (MBI) uses an injected radiotracer to evaluate blood flow and mitochondrial activity in the breast to detect cancer. Because it is a functional test, it has become a useful supplemental screening technique for women with dense breasts and an average lifetime breast cancer risk.¹⁸ MBI has been shown to detect additional foci of cancer in 9% of newly diagnosed patients and has a sensitivity of 95% in both dense and non-dense-breasted women.¹⁹ MBI can also be a useful adjunct imaging study for women with abnormal breast imaging who wish to avoid biopsy, if possible. 

Women who are deemed to have a high lifetime breast cancer risk should be referred to a medical oncologist or breast surgeon to discuss chemoprevention (e.g., using ER modulators and aromatase inhibitors) to reduce their risk.²⁰ Surgical referral should also be provided for women with an inherited genetic mutation to discuss the need for prophylactic mastectomies. Risk-reducing mastectomies have been shown to decrease incidence of, and death from, breast cancer in these women; however, they should be thoroughly counseled regarding their individual risks based on their genetics as well as their other risk factors.²¹

Fibrocystic disease
Benign breast masses can also cause significant anxiety for patients. Fibrocystic disease is one of the most common causes of breast pain. It is associated with the menstrual cycle and tends to cause pain 3 to 5 days before menstruation. Women may present with a severe exacerbation of pain and redness overlying a palpable cyst, consistent with cyst rupture. After imaging has been performed to rule out malignancy, supportive care with nonsteroidal anti-inflammatory drugs and heating pads to the breast as well as a supportive bra remains mainstays of treatment. Abstinence from caffeine and chocolate may also improve symptoms. Surgical excision is considered in women with lesions larger than 2.5 cm or that are painful.²²

Take-home message
Healthy lifestyle habits including exercise, adherence to a low-saturated-fat, high-fiber diet, maintaining a normal BMI, refraining from smoking and excess alcohol use are often easier said than done but will reduce the occurrence of a host of health problems including breast cancer. Limiting exposure to exogenous estrogens and progestins, especially in the perimenopausal period, is also a reasonable prevention strategy. Women at average risk of breast cancer should start annual screening mammograms at age 40, be screened biannually starting at age 50 through age 74 and continued thereafter until they have a less than 10-year life expectancy, at which time a discussion should be had regarding risks and benefits of continued screening. Women deemed to have a greater than 20% lifetime risk of breast cancer based on personal and family history and genetic testing should be counseled on high-risk screening, including the addition of annual MRI to annual mammograms, as well as chemoprevention and, where indicated, surgical prophylaxis.

References:

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• Mørch LS, Skovlund CW, Hannaford PC, Iversen L, Fielding S, Lidegaard Ø. Contemporary hormonal contraception and the risk of breast cancer.  N Engl J Med. 2017 Dec 7;377(23):2228-2239. 

• Jung S, Wang M, Anderson K, et al. Alcohol consumption and breast cancer risk by estrogen receptor status: in a pooled analysis of 20 studies. Int J Epidemiol. 2016 Jun;45(3):916-28. 

• Neuhouser ML, Aragaki AK, Prentice RL, et al.  Overweight, obesity, and postmenopausal invasive breast cancer risk: A secondary analysis of the women’s health initiative randomized clinical trials. JAMA Oncol. 2015 Aug;1(5):611-621. 

• Jochems SHJ, Van Osch FHM, et al.  Impact of dietary patterns and the main food groups on mortality and recurrence in cancer survivors: a systematic review of current epidemiological literature. BMJ Open. 2018 Feb 19;8(2):e014530. 

• Expert Panel on Breast Imaging: Mainiero MB, Moy L, Baron P, et al. ACR Appropriateness Criteria® Breast Cancer Screening. J Am Coll Radiol. 2017 Nov;14(11S):S383-S390. 

• Moskowitz CS, Chou JF, Wolden SL, et al.  Breast cancer after chest radiation therapy for childhood cancer. J Clin Oncol. 2014 Jul 20;32(21):2217-23. 

• Brentnall AR, Cuzick J, Buist DSM, Bowles EJA. Long-term accuracy of breast cancer risk assessment combining classic risk factors and breast density. JAMA Oncol. 2018 Sep 1;4(9):e180174. 

• Barke LD, Freivogel ME. Breast cancer risk assessment models and high-risk screening. Radiol Clin North Am. 2017 May;55(3):457-474. doi: 10.1016/j.rcl.2016.12.013. Review. 

• Shermis RB, Redfern RE, Burns J, Kudrolli H.  Molecular breast imaging in breast cancer screening and problem solving. Radiographics. 2017 Sep-Oct;37(5):1309-1606.

• Huppe AI, Mehta AK, Brem RF. Molecular breast imaging: a comprehensive review. Semin Ultrasound CT MR. 2018 Feb;39(1):60-69. 

• Visvanathan K, Hurley P, Bantug E, et al. Use of pharmacologic interventions for breast cancer risk reduction: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2013 Aug 10;31(23):2942-62. Review. Erratum in: J Clin Oncol. 2013 Dec 1;31(34):4383.

• Carbine NE, Lostumbo L, Wallace J, Ko H. Risk-reducing mastectomy for the prevention of primary breast cancer. Cochrane Database Syst Rev. 2018 Apr 5;4:CD002748. 

• Hubbard JL, Cagle K, Davis JW, Kaups KL, Kodama M. Criteria for excision of suspected fibroadenomas of the breast. Am J Surg. 2015 Feb;209(2):297-301. 

• Daly M et al. NCCN Clinical Practice Guidelines in Oncology®: Genetic/Familial High-Risk Assessment: Breast and Ovarian. V 2.2019. 7/30/2018. Available at http://www.nccn.org.