Multimodal Care Marks the Past, Present, and Future of Localized Breast Cancer Management

Joseph A. Sparano, MD

Improvements in screening, systemic therapy, and precision medicine have reduced breast cancer mortality and morbidity, said Joseph A. Sparano, MD, who added that further progress will hinge on the use of circulating tumor DNA and circulating tumor cells for disease monitoring, continued development of novel antiestrogenic agents, and movement of antibody-drug conjugates (ADCs) and immunotherapy into expanded settings and indications.

“The progress we’ve made in the past 40 years in the management of breast cancer, [in] both early and advanced stage disease, is astonishing. There’s been a 40% decline in breast cancer mortality rates. This has been due largely to the widespread adoption of screening and the use of adjuvant systemic therapies. In addition, we have had substantial advances in systemic therapies, particularly in the past 5 or so years. We’ve also seen advances in local therapy, including de-escalation of surgery and better radiation techniques. Finally, there’s been the evolution of molecular diagnostic testing, which is now widespread where one can identify both germline and somatic mutations,” Sparano said during the Ezra M. Greenspan Memorial Lecture delivered during the 41st Annual CFS®.

Sparano is the Ezra Greenspan MD Professor in Clinical Cancer Therapeutics, chief of the Division of Hematology and Oncology at the Icahn School of Medicine at Mount Sinai, and deputy director of the Tisch Cancer Institute in New York, New York.

Screening

Findings from pooled studies spanning the past 5 decades consistently show improvements in breast cancer mortality with mammography screening, Sparano explained. In a model published in the New England Journal of Medicine in 2005, authors showed a significant reduction in the rate of death from breast cancer with screening, which was further reduced with the addition of systemic therapy.2 However, screening/diagnostic mammograms and biopsies took a hit during the COVID-19 pandemic, reaching lows of 10,000 and 2,000, respectively, in April 2020, from previous peaks as high as 280,000 and 12,000 in months prior.3

“Modeling demonstrates the potential detrimental impact of this delay in screening and biopsy that could contribute to higher breast cancer mortality rates, so we need to be cognizant of this,” Sparano said.

Systemic Therapy

Prior to work done by Bernard Fisher, MD, beginning in the 1980s, radical surgery was thought to provide the best chance of cure for patients with breast cancer. However, Fisher contended that breast cancer is a systemic disease from its inception, later showing that the risk of recurrence could pose a threat to patients decades after diagnosis.4 Once radiation had proven effective in substantially reducing the risk of recurrence following lumpectomy, the notion of adjuvant chemotherapy was introduced, which proceeded to show consistent reductions in breast cancer recurrence and mortality irrespective of age, nodal status, and hormone receptor status.5 The next turning point for the field happened with the widespread use of neoadjuvant therapy and the realization that pathologic complete response not only represented a surrogate for long-term outcome but a biomarker that could be used to test and later direct more effective adjuvant therapy options. Prime examples include ado-trastuzumab emtansine (Kadcyla), which demonstrated a 50% reduction in the risk of invasive disease vs trastuzumab (Herceptin) in patients with HER2-positive disease, and capecitabine (Xeloda), which reduced the risk of recurrence, second cancer, or death by 42% vs control in patients with triple-negative breast cancer (TNBC).6,7

“The other important and foundational aspect in the management of estrogen receptor–positive breast cancer is the use of anti-estrogen therapy for 30 or 40 years, and in the past decade the use of the CDK4/6 inhibitors,” Sparano said. First approved for use in the metastatic setting, CDK4/6 inhibitors are now making their way into the adjuvant setting, Sparano noted, citing monarchE (NCT03155997), the first randomized, phase 3 trial to show benefit in distant recurrence–free survival with the addition of a CDK4/6 inhibitor to endocrine therapy. Now with 4 years of follow-up, findings continue to show reduction in the risk of distant recurrence of 34.1% vs endocrine therapy alone.8

“When many of us saw this data initially after a median follow-up of less than 2 years, we were quite concerned that these curves may come together with more time, and that we were just suppressing the growth of a dormant disease and not potentially eradicating disease. But with longer follow-up, we’re seeing continued separation of the curves, which is quite encouraging,” Sparano said.

Within the HER2-positive realm, Sparano reviewed the discovery of the HER2/neu oncogene in the mid 1980s, which led to seminal publications of HER2-directed monoclonal antibodies plus chemotherapy showing improved overall survival (OS) vs chemotherapy alone in the metastatic setting.9

“The first results became available [around] 2000, demonstrating that the addition of trastuzumab to paclitaxel in patients with HER2-overexpressing metastatic breast cancer improved median OS. The key to its success was the fact that there was a biomarker used to select a population most likely to benefit from therapy,” Sparano said.

“In addition, very recently, we’ve seen that the ADCs can also be very effective in treating [patients with] advanced disease,” Sparano said. Most recently, findings from the phase 3 DESTINY-Breast03 trial (NCT03529110) showed a 45% reduction in the risk of death with use of fam-trastuzumab deruxtecan-nxki (Enhertu) vs trastuzumab emtansine in patients with second-line metastatic, HER2-positive breast cancer, with 12-month OS rates of 94.1% (95% CI, 90.3%-96.4%) and 85.9% (95% CI, 80.9%-89.7%), respectively.10

“Another critical turning point was the realization that one can block immune checkpoints,” Sparano said, adding that there are now 2 approved indications for immunotherapy with pembrolizumab (Keytruda) plus chemotherapy in early-stage and advanced TNBC having shown improvements in event-free survival (HR, 0.63; 95% CI, 0.48-0.82; P =.00031) and OS (HR, 0.73; 95% CI, 0.55-0.95; two-sided P =.0185), respectively, vs chemotherapy alone––the latter specifically in patients with a PD-L1 combined positive score of 10 or more.11,12

Sparano also briefly touched on the use of PARP inhibitors, showcasing data from the phase 3 OlympiAD (NCT02000622) and OlympiA (NCT02032823) trials, in which treatment with olaparib (Lynparza) led to improvements in progression-free survival vs chemotherapy and invasive-disease-free survival vs placebo in the early-stage (HR, 0.58; 95% CI, 0.43-0.80; P =.0009) and advanced (HR, 0.58; 95% CI, 0.41-0.82; P <.0001) BRCA1/2-mutant, HER2-negative disease settings, respectively.13,14

“We have new tools that we’re just on the cusp of beginning to understand how to use that have demonstrated analytic and clinical validity but [have left us] unsure about their clinical utility,” Sparano said. Such tools include the RSClin tool, which has been shown to estimate the 10-year risk of distant recurrence with and without adjuvant chemotherapy, building on earlier findings from the phase 3 TAILORx trial (NCT00310180), which showed that not all patients require adjuvant chemotherapy.15,16

“We have novel antiestrogenic agents for ESR1-mutant cancers. We have ADCs that have had a dramatic impact on the advanced disease setting. There’s also the potential for broadening indications for more effective and less toxic therapies in a growing cancer survivorship population,” Sparano concluded.

References

1. Sparano JA. Management of localized breast cancer: looking back and peering ahead. Presented at: 41st Annual CFS®; November 8-10, 2023; New York, NY.
2. Berry DA, Cronin KA, Plevritis SK, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med. 2005;353(17):1784-1792. doi:10.1056/NEJMoa050518
3. Grimm LJ, Lee C, Rosenberg RD, et al. Impact of the COVID-19 pandemic on breast imaging: an analysis of the National Mammography Database. J Am Coll Radiol. 2022;19(8):919-934. doi:10.1016/j.jacr.2022.04.008
4. Fisher B, Anderson S, Bryant J, 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. 2002;347(16):1233-1241. doi:10.1056/NEJMoa022152
5. Early Breast Cancer Trialists’ Collaborative Group. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2012;379(9814):432-444. doi:10.1016/S0140-6736(11)61625-5
6. Von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628. doi:10.1056/NEJMoa1814017
7. Masuda N, Lee SJ, Ohtani S, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017;376(22):2147-2159. doi:10.1056/NEJMoa1612645
8. Johnston SRD, Toi M, O’Shaughnessy J, et al. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023;24(1):77-90. doi:10.1016/S1470-2045(22)00694-5
9. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365(14):1273-1283. doi:10.1056/NEJMoa0910383
10. Cortes J, Kim SB, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med. 2022;386(12):1143-1154. doi:10.1056/NEJMoa2115022
11. FDA approves Keytruda (pembrolizumab) for treatment of patients with high-risk early-stage triple-negative breast cancer in combination with chemotherapy as neoadjuvant treatment, then continued as single agent as adjuvant treatment after surgery. News release. Merck. July 27, 2021. Accessed November 10, 2023. https://www.merck.com/news/fda-approves-keytruda-pembrolizumab-for-treatment-of-patients-with-high-risk-early-stage-triple-negative-breast-cancer-in-combination-with-chemotherapy-as-neoadjuvant-treatment-then-continued/
12. Cortes J, Rugo S, Cescon DW, et al. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancerl. N Engl J Med. 2022;387(3):217-226. doi:10.1056/NEJMoa2202809
13. Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523-533. doi:10.1056/NEJMoa1706450
14. Tutt ANJ, Garber JE, Kaufman B, et al. Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med. 2021;384(25):2394-2405. doi:10.1056/NEJMoa2105215
15. Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379(2):111-121. doi:10.1056/NEJMoa1804710
16. Sparano JA, Crager MR, Tang G, et al. Development and validation of a tool integrating the 21-gene recurrence score and clinical-pathological features to individualize prognosis and prediction of chemotherapy benefit in early breast cancer. J Clin Oncol. 2021;39(6):557-564. doi:10.1200/JCO.20.03007