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Breast Cancer: Screening and Early Diagnosis

Breast cancer is the most common type of cancer and the second leading cause of cancer death for women in the United States.1 Fortunately, breast cancer can be treated, and early diagnosis leads to better outcomes.2-4

Screening mammography for women with an average risk of developing breast cancer reduces rates of advanced and fatal breast cancers.4 Identifying individuals with risk factors leads to early diagnosis through providing appropriate risk-based screening.5,6 For example, approximately 5% to 10% of breast cancer cases are hereditary.7,8 Consequently, genetic testing can identify women, as well as men, who are at increased risk.7,8 These individuals may benefit from more frequent surveillance or from risk reducing-treatments.7,8

This article will discuss breast cancer screening, diagnosis, and how diagnosis at an early stage can improve outcomes. Although this article uses the terms womanfemaleman, and male to reflect language in source materials, healthcare professionals should also consider the needs of transgender and gender-diverse individuals in terms of counseling, screening, and treatment.

Breast cancer epidemiology and survival

The Centers for Disease Control and Prevention (CDC) estimates that each year in the United States around 255,000 women are diagnosed with breast cancer, and approximately 42,000 will die from the disease.2 Men can also get breast cancer, although much less commonly; about 1 of every 100 breast cancers are in men.2

Approximately half (52%) of all breast cancers occur in women 55 to 74 years of age.9 However, breast cancer also occurs in younger women: approximately 27% of breast cancers occur in women 35 to 54 years of age.9 About 9% of all new cases are found in women <45 years of age.10 Notably, breast cancer in young women tends to be found at a later stage, be more aggressive, and be difficult to treat.10

The 5-year relative survival rate for all women diagnosed with breast cancer is approximately 91% (2012-2018).9 However, survival decreases markedly with more advanced-stage disease (Table).

Table. Female Breast Cancer Stage at Diagnosis, and 5-Year Relative Survivala

Stage at diagnosis9 Percent of cases 5-Year relative survival
Localized: confined to the primary site (stage I/II) 64% 99%
Regional: spread to regional lymph nodes (stage III) 29% 86%
Distant: cancer has metastasized (stage IV) 6% 30%
Unknown: unstaged 2% 60%

a Relative survival: a method of comparing the survival of people with a specific disease with those who do not have the disease. Relative survival is calculated by dividing the percentage of patients with the disease who are still alive at the end of time period (in this case 5 years) by the percentage of people in the general population of the same sex and age who are alive at the end of the same time period.

Assessing breast cancer risk

Two important risk factors for breast cancer are advanced (≥50 years) age and presence of inherited variants in the breast cancer susceptibility 1 and 2 genes (BRCA1/2), which account for 20% to 25% of hereditary breast cancers.2,11 Other genes are associated with hereditary breast cancer, and the most established associations are with variants of ATM, BARD1CDH1CHEK2NF1PALB2PTENSTK11, and TP53.11

While older age and hereditary gene variants are important risk factors for developing breast cancer, other factors associated with increased risk that all women should be aware of include2,11

  • Menstruation starting before 12 years of age
  • Menopause starting after 55 years of age
  • Dense breasts
  • Previous treatment with radiation therapy to the chest
  • Diet and lifestyle: smoking, excessive alcohol, physical inactivity, overweight
  • Family history: close relatives with certain types of cancer

Professional organizations recommend that primary care providers assess whether women or men are at increased risk of having mutations in BRCA1/2 based on personal or family history.7,11,12 The risk of having a gene variant associated with hereditary breast cancer is higher in individuals with7,11,12

  • A personal or family history of
    • Breast cancer at <50 years
    • Cancer involving both breasts
    • BRCA-related cancer (ie, breast, ovarian, pancreatic, prostate)
    • A rare cancer, such as sarcoma
  • A male family member with breast cancer
  • Multiple family members with breast cancer
  • Ashkenazi Jewish ethnicity

Tools to help assess risk include the National Cancer Institute Breast Cancer Risk Assessment Tool, commonly known as the Gail model (BCRisktool.Cancer.gov). Quest Diagnostics also has an online quiz for individuals to help determine if they are at increased risk of hereditary cancer (QuestHereditaryCancer.com).

Breast cancer screening guidelines

The American Cancer Society (ACS)3 and National Comprehensive Cancer Network® (NCCN),as well as other professional organizations, provide breast cancer screening guidelines.13 Mammography is the most common screening method, but education about breast cancer (breast cancer awareness) and breast self-examination is also important for many women.3,5,14

Digital breast tomosynthesis (DBT), also known as 3-dimensional (3D) mammography, is recommended for women with dense breasts and others with increased risk of developing breast cancer.5 This method uses a series of 2-dimensional images to build a 3D image of the breast.5,14 Other screening methods recommended for women with dense breasts and others at increased risk include breast magnetic resonance imaging (MRI) and ultrasound.5,14

ACS and NCCN screening guidelines for women with average and increased risk of breast cancer are summarized in the Sidebar.3,5

Notably, while NCCN and other professional organizations recommend clinical breast examinations and/or breast self-examination,5,14 the ACS does not recommend them for women with average risk of breast cancer.3  The ACS, however, indicates that healthcare providers may still offer clinical breast exams, along with providing counseling about risk and early detection of breast cancer to women with increased risk.

Diagnosis and prognostic markers

A definitive diagnosis of breast cancer requires histopathological examination of a tissue specimen.12,15 Once breast cancer is diagnosed, studies to determine the stage are performed (eg, lymph node and distant organ metastasis).12,15

Prognostic markers that can help to determine the best treatment and predict survival include

  • Histological type/grade:
    • Of the >20 histologic types of invasive breast cancer, the most common is infiltrating ductal carcinoma‐no special type (IDC‐NST, 70%-80% of all invasive cancers), followed by invasive lobular carcinomas (ILC, around 10% of all invasive cancers).16
    • Grade of breast cancer is established using histologic characteristics of tubule formation, nuclear pleomorphism, and mitotic activity to assign a score of 3 to 9 (Nottingham histological score)—a total score of 3 to 5 is considered Grade I (well differentiated), 6 to 7 Grade II (moderately differentiated), and 8 to 9 Grade III (poorly differentiated); Grade III is associated with the worst prognosis.16
  • Estrogen receptor (ER): Expression of ER is predictive of potential benefit from adjuvant endocrine therapy for risk reduction and local recurrence risk prevention. ER-positive breast cancer is associated with a lower recurrence rate.17
  • Progesterone receptor (PR): Expression of PR is a prognostic marker only in ER-positive cancers.17
  • Human epidermal growth factor receptor-2 (HER-2): Expression of HER-2 is predictive of potential benefit from HER-2 targeted therapy plus chemotherapy and prognostic of aggressive behavior and increased risk of recurrence and progression.17
  • Ki-67: Overexpression of Ki-67, a nuclear protein, is associated with cellular proliferation (higher value, greater proliferation, and worse prognosis). Patients with ER-positive, HER-2–negative, lymph node–positive disease with a Ki-67 ≥20% are candidates for the addition of abemaciclib to endocrine therapy.17
  • PIK3CA variant: PIK3CA is the most commonly mutated gene in ER-positive/HER-2-negative advanced breast cancer. PIK3CA variants are predictive of benefit from alpelisib with fulvestrant therapy.17
  • Triple-negative breast cancer (TNBC): ER/PR/HER-2–negative disease (ie, TNBC) accounts for 15% of invasive breast cancers.18 This very aggressive type of breast cancer is associated with advanced stage at initial diagnosis, earlier recurrence with metastatic spread, and lower overall survival.18 Certain TNBC patients may be eligible for immune checkpoint inhibition therapy with Keytruda® (pembrolizumab). TNBC is more common in premenopausal women, African American women, and BRCA1/2 carriers.18
  • Breast cancer prognostic algorithmic tests: Algorithmic-based prognostic tests to assess risk of distant recurrence and provide additional information to guide decisions on systemic therapy.5
  • Liquid biopsy: Use of blood, or other body fluids, to analyze tumor-derived DNA, RNA, or intact tumor cells. Although its clinical use is currently limited, this approach holds promise for monitoring treatment response and predicting disease progression or relapse.19

Screening guidelines for women at average risk of breast cancer

ACS recommendations for breast cancer screening among women at average risk vary by age:

  • Age 40 to 44 years: yearly screening mammograms optional.
  • Age 45 to 54 years: yearly mammograms.
  • Age 55 years and older: continual annual mammograms or switch to every other year. Screening should continue as long as a woman is in good health and is expected to live at least 10 more years.

According to the ACS, women are considered to be at average risk if they do not have a personal history of breast cancer, a strong family history of breast cancer, or a hereditary genetic variant known to increase risk of breast cancer, and have not had chest radiation therapy before the age of 30.3

The NCCN recommends clinical encounters beginning at age 25 that include a clinical breast examination and education regarding breast cancer awareness.5 Beginning at age 40, an annual clinical encounter, screening mammogram, and breast cancer awareness education are recommended. If available, DBT (ie, 3D mammography) is recommended for all women.5

Screening guidelines for women with increased risk of breast cancer

The ACS recommends that women at increased risk for breast cancer should receive a yearly mammogram and breast MRI beginning at age 30.Women at increased risk include those who

  • Have a lifetime risk of breast cancer of 20% to 25% or greater, according to risk assessment tools that are based mainly on family history
  • Have a BRCA1 or BRCA2 gene variant based on genetic testing
  • Have a first-degree relative (parent, brother, sister, or child) with a BRCA1 or BRCA2 gene variant and have not had genetic testing themselves
  • Had radiation therapy to the chest between the ages of 10 and 30 years
  • Have Li-Fraumeni syndrome, Cowden syndrome, or Bannayan-Riley-Ruvalcaba syndrome, or have first-degree relatives with one of these syndromes

The ACS does not recommend MRI screening for women whose lifetime risk of breast cancer is <15%.3

The NCCN screening recommendations are complex and depend on the causes for increased risk in individuals.In general, yearly assessments including mammography, DBT, ultrasound, and MRI are recommended depending on the reason(s) for the increased risk and residual lifetime risk.5

According to the NCCN, the age at which the assessments should begin also depends on the reason(s) for the increased risk and residual lifetime risk. The guidelines also include recommendations for risk reduction treatments in certain cases (eg, prophylactic mastectomy for women with BRCA1/2 gene variants).

How the laboratory can help

Quest Diagnostics offers testing to assist in assessing breast cancer risk, diagnosis, and prognosis. Quest also offers advanced testing that can help guide systemic therapies, including

  • Programmed death ligand 1 (PD-L1) expression testing for immune checkpoint inhibition therapy
  • BRCA1/2 germline mutation testing
  • Multigene expression panels
  • Microsatellite instability/mismatch repair (MSI/MMR) and tumor mutation burden tests

For more information on available tests and panels see

Testing for both common (eg, BRCA1 and BRCA2) and rare gene variants associated with breast cancer is also available, as well as options for testing for gene variants associated with other hereditary cancers. For more information on available tests and panels see

Board-certified genetic counselors are also available for consultation with healthcare providers at 1.866.GENE.INFO (1.866.436.3463) or at GeneInfo@QuestDiagnostics.com.

References

1. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7-33. doi:10.3322/caac.21654

2. Breast cancer awareness. Centers for Disease Control and Prevention. Reviewed September 20, 2021. Accessed August 8, 2022. https://www.cdc.gov/cancer/dcpc/resources/features/breastcancerawareness/index.htm

3. American Cancer Society recommendations for the early detection of breast cancer. Revised January 14, 2022. Accessed September 2, 2022. https://www.cancer.org/cancer/breast-cancer/screening-tests-and-early-detection/american-cancer-society-recommendations-for-the-early-detection-of-breast-cancer.html

4. Duffy SW, Tabár L, Yen AM, et al. Mammography screening reduces rates of advanced and fatal breast cancers: results in 549,091 women. Cancer. 2020;126(13):2971-2979. doi:10.1002/cncr.32859

5. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Breast cancer screening and diagnosis. Version 1.2022. Accessed August 8, 2022. https://www.nccn.org

6. Onishi N, Kataoka M. Breast cancer screening for women at high risk: review of current guidelines from leading specialty societies. Breast Cancer. 2021;28(6):1195-1211. doi:10.1007/s12282-020-01157-1

7. Genetics of breast and gynecologic cancers (PDQ®)–health professional version. National Cancer Institute. Updated April 20, 2022. Accessed August 8, 2022. https://www.cancer.gov/types/breast/hp/breast-ovarian-genetics-pdq

8. Ramya Sree PR, Thoppil JE. An overview on breast cancer genetics and recent innovations: literature survey. Breast Dis. 2021;40(3):143-154. doi:10.3233/BD-201040

9. Cancer stat facts: female breast cancer. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Accessed August 8, 2022. https://seer.cancer.gov/statfacts/html/breast.html

10. Breast cancer in young women. Centers for Disease Control and Prevention. Reviewed September 27, 2021. Accessed August 8, 2022. https://www.cdc.gov/cancer/breast/young_women/bringyourbrave/breast_cancer_young_women/index.htm

11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Genetic/familial high-risk assessment: breast, ovarian, and pancreatic. Version 1.2023. Updated September 7, 2022. Accessed September 7, 2022. http://www.nccn.org

12. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Breast Cancer. Version 4.2022. Updated June 21, 2022. Accessed September 4, 2022. http://www.nccn.org

13. Qaseem A, Lin JS, Mustafa RA, et al. Screening for breast cancer in average-risk women: a guidance statement from the American College of Physicians. Ann Intern Med. 2019;170(8):547-560. doi:10.7326/M18-2147

14. Narayan AK, Lee CI, Lehman CD. Screening for breast cancer. Med Clin North Am. 2020;104(6):1007-1021. doi:10.1016/j.mcna.2020.08.003

15. Cardoso F, Kyriakides S, Ohno S, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019;30(8):1194-1220. doi:10.1093/annonc/mdz173

16. Tsang JYS, Tse GM. Molecular classification of breast cancer. Adv Anat Pathol. 2020;27(1):27-35. doi:10.1097/PAP.0000000000000232

17. Najjar S, Allison KH. Updates on breast biomarkers. Virchows Arch. 2022;480(1):163-176. doi:10.1007/s00428-022-03267-x

18. Sukumar J, Gast K, Quiroga D, et al. Triple-negative breast cancer: promising prognostic biomarkers currently in development. Expert Rev Anticancer Ther. 2021;21(2):135-148. doi:10.1080/14737140.2021.1840984

19. Tay TKY, Tan PH. Liquid biopsy in breast cancer: a focused review. Arch Pathol Lab Med. 2021;145(6):678-686. doi:10.5858/arpa.2019-0559-RA

Models used for illustrative purposes.

Published date: Oct 2022

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