The sustained drop in breast cancer mortality over the last 30 years is largely due to enhanced screening and significant treatment improvements ^1-3.

Breast screening has been widely adopted in the United States with nearly 65% of the eligible population undergoing examination. Evolving technologic advancements have also increased the sensitivity and specificity of screening evaluations^3-6. Some of the available screening tools, like digital 2D mammograms have become increasingly cost-effective. Yet others, such as breast MRI, remain expensive, time consuming, and unpleasant for patients. Confusion has also resulted from evolving changes in national guidelines and conflicting recommendations for patients and providers. This has introduced uncertainty as to who should be screened, when they should be screened , and how often should they be screened ^7-9.

It has become increasingly evident that breast cancer screening should not be a “one-size-fits all” proposition. For some, low-intensity screening with mammography may be sufficient. For others, ultrasound and even MRI should be a routine. Similarly, the ages at which screening starts and ends should not be absolute, but should depend on underlying health, risk, and desired endpoints. The goals of screening are different among different stakeholders. Many forget that the classic endpoint of a screening program is mortality reduction per 100,000 population.¹⁰ But other valuable outcomes are not captured solely by changes in mortality. These include the de-escalation of therapy and the concomitant reduction in morbidity, anxiety, and cost frequently associated with making an earlier diagnosis.

The mathematics of effective screening depend on any test’s sensitivity, its specificity, the incidence of the target disease, and an individual’s unique risk of disease¹¹. If the disease is rare, or an individual’s risk is low, then even a screening test with high-sensitivity and specificity may be unreasonable. In low prevalence settings, screening-associated anxiety, costs, and the incidence of over-diagnosis and over-management may predominate. Alternatively, as a disease becomes more prevalent, variations in individual risk can, and should, lead to varied recommendations for the screening technology utilized, as well as for screening incidence, frequency, and intervals. A modern screening program should take into account all of these variables, and assess all participants for individual risk, optimizing both efficacy and efficiency.

Large population risk assessment has not been an integral part of most screening programs. Occasionally individuals may initiate online testing from direct-to-consumer companies like 23 And Me which will inform them of unique genetic risks. Some may be prompted to obtain limited genetic testing by their physicians ^12-15. However, the majority of genetic or algorithm-based evaluations usually occur only after a new personal cancer diagnosis, or a new cancer diagnosis in a close relative.

Even when a high-risk score is derived from a risk-assessment calculator, or from a genetic mutational analysis, most communities have limited resources for evaluation and management of affected patients. Full-time genetic counselors are rare, and few clinical settings exist for high-risk individuals to pursue meaningful follow-up. As a result, mutations in high-risk genes, like BRCA-1 and BRCA-2, often lead to an assumed need for prophylactic surgery. When lower-risk genetic anomalies are discovered most patients are left with unanswered questions and inconsistent or inadequate follow-up. It is precisely these patients who should be considered for enhanced screening and medical prevention strategies. As a result, patients should seek, and practitioners should provide, appropriate high-risk assessment and monitoring clinics where these needs can be readily addressed.

Once, breast cancer is diagnosed, knowing which genes are turned-on (expressed) or turned-off (repressed) may provide a window into the biological behavior of an individual cancer. This is known as gene expression profiling (GEP). When suitably validated GEP can predict the likelihood of local and distant tumor recurrence, as well as long term prognosis¹⁶. GEP testing may also provide predictive information about a tumor’s likely response to chemotherapy, immunotherapy, or hormonal manipulation¹⁷. By employing such tools, unnecessary or ineffective therapies may be avoided.

The up-front risk assessment of local recurrence by GEP may also shape and guide preoperative treatment, choice of operative procedure, as well as the utility of postoperative adjunctive treatments like radiation therapy, chemotherapy, and endocrine (hormonal) therapy. ^18-20

But GEP performed on a primary tumor may be supplanted as new techniques evolve. Recent technologic advances have led to a growing interest, and growing capability, in performing serum-based genomic testing. These so-called “liquid biopsies” aim to detect circulating tumor cells (CTCs), or circulating tumor DNA (ctDNA), and cell-free RNA released during tumor cell turnover. Any of these may appear in the circulation of a cancer patient in minute quantities ^21-23. Thus far, this technology has largely been confined to patients with advanced cancers where the tumor burden is high. In this setting, the measured material has already been shown to predict response to certain systemic therapies, while serving as a monitor of overall patient progress.

However, the next step is just becoming available and consists of the detection of so-called “minimal residual disease” (MRD). This concept may change the paradigm of solid tumor management. Currently, patients are treated with drug therapy after surgery because of the statistical likelihood of residual disease based on primary tumor size and the presence of lymph node metastasis. However, this leads to treatment of many patients who do not actually have residual malignancy, in the hopes of improving outcome for the small percentage that do. Furthermore, when treatment is employed, it is largely based on characteristics of the primary tumors that may be substantively different from their micrometastatic progeny.

The ability to measure MRD after surgery allows the identification of individuals who continue to need treatment; analysis of the genomics of that MRD may further identify the specific agent that is most likely to be effective. Re-testing for MRD after first-round systemic drug therapy, may further serve as an identifier of patients who continue to need more therapeutic intervention. Alternatively, patients without circulating evidence of disease may someday receive simple observation and monitoring against the day when tumor-associated substances may be found in the circulation. Only then might those individuals with newly discovered MRD receive toxic or expensive treatments, including chemotherapy or immunotherapy. The day is fast approaching when liquid biopsy surveillance of MRD may be the chief determinate of who gets adjunctive drug therapy, and when they get it.

Although there has been interest in liquid biopsy for screening of cancer, this still remains somewhat in the future ^24-25. Not only must the sensitivity and specificity be significantly higher than current technology generally allows, but localization of the source of a “detected” subclinical tumor would be problematic. A marker suggesting the presence of a cancer, without a site of origin, may be helpful for enhanced radiologic screening, but might not allow practical surgical or radiotherapeutic intervention. However, such individuals, may be candidates for minimally intrusive drug prevention or drug treatment strategies.

In an era of rapidly changing technology, it is important to have available the most efficient tools for screening and early detection, and to use those tools appropriately. Once cancer is diagnosed, it is important to have a thorough understanding of an individual’s tumor biology and tumor behavior. Only then can appropriate and effective surgical, radiation, and pharmaceutical therapies be optimally employed.

Although today’s therapies are most commonly recommended because a patient fits into a broad risk category, in future the choice of treatment is more likely to be based on the unique needs of the individual patient, the actual tumor burden, and the specific biology of any tumor present. Working together in this brave new world of personalized cancer care, specialty breast surgical and medical oncologists will be able to guide patients along a pathway in which unnecessary treatment and toxicity are minimized, and function, aesthetics, and outcome are optimized.

REFERENCES:

1. Ahmad A. Breast Cancer Statistics: Recent Trends. Adv Exp Med Biol.2019;1152:1-7. doi: 10.1007/978-3-030-20301-6_1. Review. PubMed PMID: 31456176.
2. Hendrick RE, Baker JA, Helvie MA. Breast cancer deaths averted over 3 decades. Cancer. 2019 May 1;125(9):1482-1488. doi: 10.1002/cncr.31954. Epub 2019 Feb 11. PubMed PMID: 30740647.
3. Kopans DB. Just the facts: mammography saves lives with little if anyradiation risk to the mature breast. Health Phys. 2011 Nov;101(5):578-82. doi:10.1097/HP.0b013e3182254e93. PubMed PMID: 21979544.
4. Niell BL, Freer PE, Weinfurtner RJ, Arleo EK, Drukteinis JS. Screening for Breast Cancer. Radiol Clin North Am. 2017 Nov;55(6):1145-1162. doi:10.1016/j.rcl.2017.06.004. Review. PubMed PMID: 28991557.
5. Fiorica JV. Breast Cancer Screening, Mammography, and Other Modalities. Clin Obstet Gynecol. 2016 Dec;59(4):688-709. Review. PubMed PMID: 27741212.
6. Partovi S, Sin D, Lu Z, Sieck L, Marshall H, Pham R, Plecha D. Fast MRI breast cancer screening – Ready for prime time. Clin Imaging. 2019 Nov 30;60(2):160-168. doi: 10.1016/j.clinimag.2019.10.013. [Epub ahead of print] Review. PubMed PMID:31927171.
7. Qaseem A, Lin JS, Mustafa RA, Horwitch CA, Wilt TJ; Clinical Guidelines
8. Committee of the American College of Physicians. Screening for Breast Cancer inAverage-Risk Women: A Guidance Statement From the American College of Physicians. Ann Intern Med. 2019 Apr 16;170(8):547-560. doi: 10.7326/M18-2147. Epub 2019 Apr 9. PubMed PMID: 30959525.
9. Ebell MH. USPSTF Recommendations: New and Updated in 2016. Am Fam Physician.2017 Dec 1;96(11):697-698. PubMed PMID: 29431399.
10. Smith RA, Andrews KS, Brooks D, Fedewa SA, Manassaram-Baptiste D, Saslow D, Wender RC. Cancer screening in the United States, 2019: A review of current American Cancer Society guidelines and current issues in cancer screening. CA Cancer J Clin. 2019 May;69(3):184-210. doi: 10.3322/caac.21557. Epub 2019 Mar 15. PubMed PMID: 30875085.
11. Stegeman I, Bossuyt PM. Cancer risk models and preselection for screening. Cancer Epidemiol. 2012 Oct;36(5):461-9. doi: 10.1016/j.canep.2012.06.010. Epub2012 Jul 25. Review. PubMed PMID: 22841151
12. https://www.23andme.com
13. https://www.bebrcaware.com/i-dont-know-my-brca-status/how-to-get-a-brca-test.html
14. https://www.invitae.com/en/physician/tests/50002/
15. Harnan S, Tappenden P, Cooper K, Stevens J, Bessey A, Rafia R, Ward S, Wong R, Stein RC, Brown J. Tumour profiling tests to guide adjuvant chemotherapy decisions in early breast cancer: a systematic review and economic analysis. Health Technol Assess. 2019 Jun;23(30):1-328. doi: 10.3310/hta23300. PubMed PMID:31264581; PubMed Central PMCID: PMC6627008.
16. Hyams DM, Schuur E, Angel Aristizabal J, Bargallo Rocha JE, Cabello C, Elizalde R, García-Estévez L, Gomez HL, Katz A, Nuñez De Pierro A. Selecting postoperative adjuvant systemic therapy for early stage breast cancer: A critical assessment of commercially available gene expression assays. J Surg Oncol. 2017 May;115(6):647-662. doi: 10.1002/jso.24561. Epub 2017 Feb 17. Review. PubMedPMID: 28211064; PubMed Central PMCID: PMC5484338.
17. Mamounas EP, Liu Q, Paik S, Baehner FL, Tang G, Jeong JH, Kim SR, Butler SM, Jamshidian F, Cherbavaz DB, Sing AP, Shak S, Julian TB, Lembersky BC, Wickerham DL, Costantino JP, Wolmark N. 21-Gene Recurrence Score and Locoregional Recurrence in Node-Positive/ER-Positive Breast Cancer Treated With Chemo-Endocrine Therapy. J Natl Cancer Inst. 2017 Jan 25;109(4). doi:10.1093/jnci/djw259. Print 2017 Jan. PubMed PMID: 28122895; PubMed Central PMCID: PMC5721938.
18. Woodward WA, Barlow WE, Jagsi R, Buchholz TA, Shak S, Baehner F, Whelan TJ, Davidson NE, Ingle JN, King TA, Ravdin PM, Osborne CK, Tripathy D, Livingston RB, Gralow JR, Hortobagyi GN, Hayes DF, Albain KS. Association Between 21-Gene Assay Recurrence Score and Locoregional Recurrence Rates in Patients With Node-Positive Breast Cancer. JAMA Oncol. 2020 Jan 9. doi: 10.1001/jamaoncol.2019.5559. [Epub ahead of print] PubMed PMID: 31917424.
19. Bhutiani N, Vuong B, Egger ME, Eldredge-Hindy H, McMasters KM, Ajkay N.Evaluating patterns of utilization of gene signature panels and impact ontreatment patterns in patients with ductal carcinoma in situ of the breast. Surgery. 2019 Oct;166(4):509-514. doi: 10.1016/j.surg.2019.04.044. Epub 2019 Jul 20. PubMed PMID: 31337506.
20. Oliveira KCS, Ramos IB, Silva JMC, Barra WF, Riggins GJ, Palande V, Pinho CT, Frenkel-Morgenstern M, Santos SEB, Assumpcao PP, Burbano RR, Calcagno DQ. Current perspectives on circulating tumor DNA, precision medicine, and personalized clinical management of cancer. Mol Cancer Res. 2020 Jan 29. pii: molcanres.0768.2019. doi: 10.1158/1541-7786.MCR-19-0768. [Epub ahead of print] PubMed PMID: 31996469.
21. Siravegna G, Mussolin B, Venesio T, Marsoni S, Seoane J, Dive C, PapadopoulosN, Kopetz S, Corcoran RB, Siu LL, Bardelli A. How liquid biopsies can change clinical practice in oncology. Ann Oncol. 2019 Oct;30(10):1580-1590. doi:10.1093/annonc/mdz227. Epub 2019 Dec 27. Review. PubMed PMID: 31987449.
22. Kelley SO, Pantel K. A New Era in Liquid Biopsy: From Genotype to Phenotype. Clin Chem. 2019 Dec 6. pii: clinchem.2019.303339. doi:10.1373/clinchem.2019.303339. [Epub ahead of print] Review. PubMed PMID:31811003.
23. Underwood JJ, Quadri RS, Kalva SP, Shah H, Sanjeevaiah AR, Beg MS, Sutphin PD. Liquid Biopsy for Cancer: Review and Implications for the Radiologist. Radiology. 2020 Jan;294(1):5-17. doi: 10.1148/radiol.2019182584. Epub 2019 Nov 19. PubMed PMID: 31746691.
24. Chen M, Zhao H. Next-generation sequencing in liquid biopsy: cancer screening and early detection. Hum Genomics. 2019 Aug 1;13(1):34. doi:10.1186/s40246-019-0220-8. Review. PubMed PMID: 31370908; PubMed Central PMCID:PMC6669976.