New frontiers in breast cancer management

For a very long time, treatment for breast cancer was simple. If your grandmother or relative was diagnosed prior to the 1960s, the only option was a radical mastectomy, and this had been the case for nearly a century since treatment began in 1882¹. Beginning in the 1960s, treatment slowly evolved, and over the next three decades, hormone therapy², radiation³, and chemotherapy⁴ were adopted into clinical practice.

But today, treatment options are evolving much more rapidly. Since the approval of the first personalized therapy for breast cancer, Herceptin^5-6 in 1998, major advances have occurred in genomic sequencing, optimization of drug pipelines, and immunotherapy. In fact, over thirty drugs and drug combinations for breast cancer were approved between 2010 and 2020⁷, and the pace is not slowing down. Indeed, in the past year alone, three new treatment options for women with challenging types of breast cancer have been approved.

Enhertu approved for HER2-low breast cancer
Herceptin specifically targets a protein on the cancer cell’s surface called human epidermal grow factor receptor 2 (HER2), and it led to vast improvements in outcomes for women diagnosed with HER2-driven breast cancer. However, not all women with detectable HER2 expression benefit from agents that target HER2. This is because, for a long time, these agents only worked when the cancer cells had a lot of HER2 expression.

Many women develop a type of breast cancer that falls into a category called HER2-low. This means there is some HER2 expression on the cancer cells, but it is not high enough to benefit from Herceptin or other agents. This has been frustrating for researchers and doctors, forcing them to rely on other features of the cancer when making treatment decisions⁸. But that recently shifted with the advent of Enhertu. Enhertu is part of a new class of drugs called antibody-drug conjugates that combine the targeting aspect of an antibody and the cancer-killing power of a chemotherapy⁹. Enhertu delivers more chemotherapy to a cancer cell, but less to the rest of the body, increasing effectiveness and alleviating some side effects.

In a landmark clinical trial called DESTINY-Breast04, treatment of HER2-low breast cancer with Enhertu resulted in a significant improvement in survival for breast cancer patients¹⁰. This led the FDA to approve Enhertu in this population in August 2022.

Elacestrant approved for ESR1 mutant breast cancer
Some breast cancers are highly dependent on estrogen signaling for tumor growth, making hormone therapy a very effective option for many women. Hormone therapies are designed to deprive cancer cells of estrogen in one of three ways; they can either block estrogen production, stop estrogen from reaching its receptor, or cause the loss of the estrogen receptor¹¹. However, cancer cells can subvert almost all of these mechanisms when a mutation in the estrogen receptor gene, called ESR1, arises during treatment¹². When this happens, the shape of the estrogen receptor changes, and it then drives cancer growth even without estrogen, rendering most of these therapies ineffective.

In 2022, results from the EMERALD clinical trial demonstrated that a new hormone therapy, called elacestrant, was effective in patients with an ESR1 mutation. Treatment with elacestrant nearly doubled the time to progression in patients with metastatic disease¹³. This drug is different than the other hormone therapies because it has a unique shape that allows it to bind to the estrogen receptor and degrade it, even with ESR1 mutations present¹⁴. In this way, it is a major breakthrough for this subset of disease and was approved in January 2023.

Trodelvy approved for advanced hormone receptor-positive breast cancer
Cancer drugs will often be approved for a specific subtype first, and then new data will emerge from other trials, prompting approval in more settings. This was the case with the antibody-drug conjugate Trodelvy. Trodelvy targets a protein called TROP2 that is expressed in many breast cancers. The drug was first shown to be effective in triple-negative breast cancer and approved for this indication in April 2021¹⁵. However, data from a large clinical trial, called TROPiCS-02, recently demonstrated that Trodelvy is more effective than standard chemotherapies for advanced, hormone receptor-positive disease. It reduced the risk of cancer-related death by 21% and elicited responses in 33% more patients¹⁶; it was approved for hormone positive breast cancer in February 2023.

Selecting a personalized treatment path can be complex
Despite the clear benefits, these advances mean that treatment for breast cancer is now quite complex. That, coupled with improved screening, means more women than ever will be faced with therapy choices, but the optimal treatment path isn’t always clear. We at PHM are here to ensure all patients with breast cancer find that path. To do this, we evaluate all the latest data, as well as collaborate with the patient’s providers to comprehensively characterize the disease, so a personalized treatment plan can be devised and implemented.

For example, subtyping using gene signatures can re-classify about a quarter of tumors and predict responses to therapy prior to surgery¹⁷. Another test that examines molecular signatures in HER2-positive cancer can predict a response to a less intense regimen and help women avoid overtreatment¹⁸. Finally, personalized blood tests that detect the presence of circulating tumor DNA can both predict risk of relapse and measure response to therapy^19-21.

By integrating these new testing strategies, patients and doctors can navigate the evolving, complex treatment landscape for breast cancer more easily. This brings us closer to achieving the best results possible for each patient.

References

1. Halsted, W. S. I. The Results of Radical Operations for the Cure of Carcinoma of the Breast. Ann Surg 46, 1-19, doi:10.1097/00000658-190707000-00001 (1907).
2. Ward, H. W. Anti-oestrogen therapy for breast cancer: a trial of tamoxifen at two dose levels. Br Med J 1, 13-14, doi:10.1136/bmj.1.5844.13 (1973).
3. Fisher, B. et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347, 1233-1241, doi:10.1056/NEJMoa022152 (2002).
4. Bonadonna, G. et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 294, 405-410, doi:10.1056/NEJM197602192940801 (1976).
5. Slamon, D. J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344, 783-792, doi:10.1056/NEJM200103153441101 (2001).
6. Romond, E. H. et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353, 1673-1684, doi:10.1056/NEJMoa052122 (2005).
7. Arora, S. et al. U.S. FDA Drug Approvals for Breast Cancer: A Decade in Review. Clin Cancer Res 28, 1072-1086, doi:10.1158/1078-0432.CCR-21-2600 (2022).
8. Peiffer, D. S. et al. Clinicopathologic Characteristics and Prognosis of ERBB2-Low Breast Cancer Among Patients in the National Cancer Database. JAMA Oncol 9, 500-510, doi:10.1001/jamaoncol.2022.7476 (2023).
9. Ferraro, E., Drago, J. Z. & Modi, S. Implementing antibody-drug conjugates (ADCs) in HER2-positive breast cancer: state of the art and future directions. Breast Cancer Res 23, 84, doi:10.1186/s13058-021-01459-y (2021).
10. Modi, S. et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med 387, 9-20, doi:10.1056/NEJMoa2203690 (2022).
11. Hernando, C. et al. Oral Selective Estrogen Receptor Degraders (SERDs) as a Novel Breast Cancer Therapy: Present and Future from a Clinical Perspective. Int J Mol Sci 22, doi:10.3390/ijms22157812 (2021).
12. Brett, J. O., Spring, L. M., Bardia, A. & Wander, S. A. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res 23, 85, doi:10.1186/s13058-021-01462-3 (2021).
13. Bidard, F. C. et al. Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial. J Clin Oncol 40, 3246-3256, doi:10.1200/JCO.22.00338 (2022).
14. Fanning, S. W., Greene, G. & Conlan, M. G. X-ray crystal structure analysis of elacestrant (RAD1901), a novel selective estrogen receptor degrader (SERD), bound to estrogen receptor alpha ligand binding domain. Journal of Clinical Oncology 38, e15647-e15647, doi:10.1200/JCO.2020.38.15_suppl.e15647 (2020).
15. Bardia, A. et al. Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. N Engl J Med 384, 1529-1541, doi:10.1056/NEJMoa2028485 (2021).
16. Rugo, H. S. et al. Primary results from TROPiCS-02: A randomized phase 3 study of sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) in patients (Pts) with hormone receptor–positive/HER2-negative (HR+/HER2-) advanced breast cancer. Journal of Clinical Oncology 40, LBA1001-LBA1001, doi:10.1200/JCO.2022.40.17_suppl.LBA1001 (2022).
17. Whitworth, P. et al. Age-Independent Preoperative Chemosensitivity and 5-Year Outcome Determined by Combined 70- and 80-Gene Signature in a Prospective Trial in Early-Stage Breast Cancer. Ann Surg Oncol 29, 4141-4152, doi:10.1245/s10434-022-11666-2 (2022).
18. Waks, A. G. et al. Assessment of the HER2DX Assay in Patients With ERBB2-Positive Breast Cancer Treated With Neoadjuvant Paclitaxel, Trastuzumab, and Pertuzumab. JAMA Oncol, doi:10.1001/jamaoncol.2023.0181 (2023).
19. Parsons, H. A. et al. Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer. Clin Cancer Res 26, 2556-2564, doi:10.1158/1078-0432.CCR-19-3005 (2020).
20. Garcia-Murillas, I. et al. Assessment of Molecular Relapse Detection in Early-Stage Breast Cancer. JAMA Oncol 5, 1473-1478, doi:10.1001/jamaoncol.2019.1838 (2019).
21. Magbanua, M. J. M. et al. Clinical significance and biology of circulating tumor DNA in high-risk early-stage HER2-negative breast cancer receiving neoadjuvant chemotherapy. Cancer Cell, doi:10.1016/j.ccell.2023.04.008 (2023).