Advanced Therapies Redefine Survival for Patients With Breast Cancer

Breast cancer (BC) is the most common malignancy in women in the United States, accounting for about 30% of cancer cases in this population. Years of advancements in BC education, screening, diagnosis, and treatment have greatly improved outcomes for patients and offer varied therapeutic options to meet their unique needs. According to the American Cancer Society, as of 2024, the chance of mortality in patients with BC is only about 2.5%; however, a population of those who are high-risk with aggressive, potentially mutated or drug-resistant disease remain.¹

The advancements in BC treatment are revolutionizing approaches in both early and metastatic disease. Image Credit: © Siam - stock.adobe.com

At the National Community Oncology Dispensing Association Fall Summit in Orlando, Joyce O’Shaughnessy, MD, hematology and oncology specialist at Texas Oncology, shared recent advancements in early and metastatic BC, focusing on benefits of adjunct CDK4/6 and checkpoint inhibitors, as well as how to decide which populations best benefit from chemotherapy (CT) and endocrine therapy (ET). Her insights and trial data provide a comprehensive view of current standards of care (SOC) and how to best navigate treatments across BC subtypes.²

Hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative (HR+/HER2–) is the most prevalent subtype of BC, accounting for nearly 70% of all new cases. Patients with this subtype have a high risk of relapse at approximately 30% by year 5. Treatment of HR+/HER2– BC can be complex due to a required multifaceted approach, especially in the presence of mutations such as BRCA1 and BRCA2, the most common cause of hereditary BC, and PIK3CA. Approximately 40% of patients with HR+/HER2– early-stage BC (EBC) have a PIK3CA mutation, which encourages metastatic growth, endocrine resistance, and progression of disease. These diverse factors underscore the heterogeneity of BC, highlighting the need for increasingly personalized and precise treatment approaches to optimize outcomes for each patient.^3,4

For patients with EBC, the most common issue faced by specialists is deciding who needs or would benefit from CT. The RxPONDER trial (NCT01272037) is evaluating ET such as tamoxifen citrate (Nolvadex; AstraZeneca AB), letrozole (Femara; Novartis), anastrozole (Arimidex; AstaZeneca), or exemestane (Aromasin; Pfizer Oncology Together), with or without CT in women with HR+/HER2, axillary lymph-node–negative BC.⁵

The trial randomized 5083 pre- and postmenopausal women (33.2% and 66.8%, respectively) to determine CT benefit, inspired by the hypothesis that CT may result in ovarian function suppression. According to the data, premenopausal women with 1 to 3 positive lymph nodes and a recurrence score of 25 or lower who received chemo-ET had longer invasive disease–free survival and distant relapse–free survival than those who received endocrine-only therapy. Although, most notably, it was shown that postmenopausal women with similar characteristics did not benefit from adjuvant CT.²

“And so, the question became ‘is CT simply acting mainly as an endocrine therapy in those [postmenopausal] patients?’ And if that was the case, we would rather not get CT to cause ovarian function suppression,” said O’Shaughnessy. “We would like to give an LHRH [luteinizing hormone-releasing hormone] agonist.”²

However, adjuvant CT may not benefit all premenopausal patients, according to findings from the post hoc analysis from RxPONDER. The data showed that anti-Mullerian hormone (AMH) levels, which indicate ovarian function, not only predicting risk of BC, but also indicate which patients will benefit from CT. Compared with patients who have medium to high levels of AMH, those with low AMH levels did not benefit from CT, suggesting that the CT may be working through ovarian function suppression.⁶

Preliminary, hypothesis-generated data from the FLEX trial (NCT03053193) regarding the use of anthracycline-based versus non-anthracycline CT regimens in HR-positive, HER2-negative EBC suggests the potential benefit of anthracycline-based CT for patients with high AMH levels. The results were determined using Mammaprint, a 70-gene prognostic assay with 4 risk categories—ultra-low, low, high 1, and high 2—which indicates the differential benefit from CT regimens.⁷

The ultra-low and low-risk groups are both ET sensitive with low metastatic potential and benefit most from extended adjuvant ET without CT. The high 1 group represents the lower 50% of the high-risk Mammaprint patients. According to O’Shaughnessy, these patients benefitted from CT in the MINDACT trial (NCT00433589); however, they do not differentially benefit from DNA damaging agents such as platinum agents, PARP inhibitors, and checkpoint inhibitors.^2,8

The high 2 group represents the highest, ultra-high-risk patients with homologous recombination deficient cancers that may benefit more from DNA-damaging agents. Data from the FLEX trial showed that adding a neoadjuvant anthracycline-based CT regimen in the high 2 group led to a 32% pathologic complete response rate compared with 0% for a non-anthracycline regimen, supporting the hypothetical benefit of anthracycline-based CT in this group.²

Adjuvant CDK4/6 inhibitors have also demonstrated success in treating patients with high-risk, HR+/HER2, node-positive EBC. When overactivated, CDK4/6 proteins encourage the rapid growth and proliferation of cancer cells, calling for treatment with agents such as abemaciclib (Verzenio; Eli Lilly) or ribociclib (Kisqali; Novartis). In the monarchE trial (NCT03155997), treatment with abemaciclib demonstrated a 5-year 7.6% absolute improvement in IDFS, compared with ribociclib, which resulted in a 4.9% absolute IDFS improvement in the NATALEE trial (NCT03701334). In both studies, dose reduction did not compromise efficacy and rather improved patient adherence.^2,9-11

High-risk, HR+/HER2- may also be treated with checkpoint inhibitors, such as pembrolizumab (Keytruda; Merck) or nivolumab (Opdivo; Bristol Myers Squibb) which have shown success in KEYNOTE-756 (NCT03725059) and CheckMate 7FL (NCT04109066). Both trials demonstrated that the benefit from checkpoint inhibitors was more pronounced in patients with high PDL1 expression and low estrogen receptor expression.^12,13

Of the 1 in 8 women who will be diagnosed with BC, 1 in 3 will develop metastatic BC (MBC) either in the lungs, liver, brain, or bones, which is the most common at nearly 70% of cases. As of 2024, a third of women with MBC have lived over 5 years with comprehensive medical interventions, calling for improved treatments that can ensure longevity and quality of life for patients.¹

The first line SOC for MBC comprises of a CDK4/6 such as palbociclib (Ibrance; Pfizer), ribociclib, or abemaciclib, which all demonstrated efficacy in improving progression-free survival by 1 year, with an aromatase inhibitor. For patients who progress after first line CDK4/6 inhibitor therapy, O’Shaughnessy, supported by data from the postMONARCH trial (NCT05169567), suggested using abemaciclib plus fulvestrant (Faslodex; AstraZeneca).¹⁵

Checkpoint inhibitors have also shown efficacy in treatment of MBC. In the phase 3 KEYNOTE 522 trial (NCT03036488), patients with previously untreated stage 2 or stage 3 triple-negative BC were randomized to receive neoadjuvant therapy with pembrolizumab (at a dose of 200 mg) every 3 weeks plus paclitaxel (Taxol; Abraxis BioScience, LLC) and carboplatin (Paraplatin; Bristol-Myers Squibb) or placebo every 3 weeks plus paclitaxel and carboplatin.^16,17

“Now we have matured 5-year data, and we can see an absolute improvement in event-free survival of 9% and we see that EMS [ethylmethane sulfonate] curve really flattening out. It really looks like this is probably a permanent 9% improvement in the cure rate for these patients,” said O’Shaughnessy. “For the first time we saw statistically significant improvement in overall survival of 4.9%, really corroborating our standard of care for these patients.”²

Patients with HER2-low, HR+/HER2, stage 4 MBC, according to data from the DESTINY-Breast04 trial (NCT03734029), experienced an improved PFS when adding an antibody drug conjugate, trastuzumab deruxtecan (Enhertu: AstraZeneca), to CT. This was also observed for patients with stage 2 and 3 diseases in the DESTINY-Breast06 trial (NCT04494425), highlighting the agent’s potential efficacy across various stages of disease.^18,19

The advancements in BC treatment, particularly in the use of targeted therapies, CDK4/6 inhibitors, and checkpoint inhibitors, are revolutionizing approaches in both early and metastatic disease. As research continues to uncover more effective combinations and therapies, patients benefit from improved survival rates and enhanced quality of life. However, with ongoing challenges in treating high-risk populations, precision medicine remains essential in delivering optimal outcomes for BC patients and continued clinical research is key to optimizing health outcomes.

REFERENCES

1. Key statistics for breast cancer. American Cancer Society. January 17, 2024. Accessed October 24, 2024. https://www.cancer.org/cancer/types/breast-cancer/about/how-common-is-breast-cancer.html

2. O’Shaughnessy J. Advances in breast cancer treatment and current updates. NCODA Fall Summit. October 24, 2024. Orlando, Florida.

3. Gerlach A. Pharmacists enhance care for patients with hr+/her2– breast cancer on cdk4/6 inhibitor therapy. Pharmacy Times. August 28, 2024. Accessed October 24, 2024. https://www.pharmacytimes.com/view/pharmacists-enhance-care-for-patients-with-hr-her2-breast-cancer-on-cdk4-6-inhibitor-therapy

4. Gerlach A. FDA grants breakthrough therapy designation to inavolisib for pik3ca-mutated breast cancer. Pharmacy Times. May 21, 2024. Accessed October 24, 2024. https://www.pharmacytimes.com/view/fda-grants-breakthrough-therapy-designation-to-inavolisib-for-pik3ca-mutated-breast-cancer

5. Tamoxifen citrate, letrozole, anastrozole, or exemestane with or without CT in treating patients with invasive rxponder breast cancer. ClinicalTrials.gov Identifier: NCT01272037. Updated October 22, 2024. Accessed October 24, 2024. https://clinicaltrials.gov/study/NCT01272037

6. Kalinsky K, Barlow W, Gralow J, et al. 21-gene assay to inform CT benefit in node-positive breast cancer. N Engl J Med. December 1, 2021. doi:10.1056/NEJMoa2108873

7. Mammaprint, blueprint, and full-genome data linked with clinical data to evaluate new gene expression profiles (flex). ClinicalTrials.gov Identifier: NCT03053193. Updated June 27, 2024. Accessed October 24, 2024. https://www.clinicaltrials.gov/study/NCT03053193

8. Genetic testing or clinical assessment in determining the need for chemotherapy in women with breast cancer that involves no more than 3 lymph nodes (mindact). ClinicalTrials.gov Identifier: NCT00433589. Updated November 17, 2022. Accessed October 24, 2024. https://clinicaltrials.gov/study/NCT00433589

9. Gerlach A. FDA approves ribociclib in combination with an aromatase inhibitor for hr+/her2- early breast cancer. Pharmacy Times. September 17, 2024. Accessed October 24, 2024. https://www.pharmacytimes.com/view/fda-approves-ribociclib-in-combination-with-an-aromatase-inhibitor-for-hr-her2--early-breast-cancer

10. Endocrine therapy with or without abemaciclib (ly2835219) following surgery in participants with breast cancer (monarche). ClinicalTrials.gov Identifier: NCT03155997. Updated October 1, 2024. Accessed October 24, 2024. https://clinicaltrials.gov/study/NCT03155997

11. A trial to evaluate efficacy and safety of ribociclib with endocrine therapy as adjuvant treatment in patients with hr+/​her2- early breast cancer (natalee). ClinicalTrials.gov Identifier: NCT03701334. Updated October 10, 2024. Accessed October 24, 2024. https://clinicaltrials.gov/study/NCT03701334

12. Study of pembrolizumab (mk-3475) versus placebo in combination with neoadjuvant chemotherapy & adjuvant endocrine therapy in the treatment of early-stage estrogen receptor-positive, human epidermal growth factor receptor 2-negative (er+/​her2-) breast cancer (mk-3475-756/​keynote-756). ClinicalTrials.gov Identifier: NCT03725059. Updated December 18, 2023. Accessed October 24, 2024. https://clinicaltrials.gov/study/NCT03725059

13. Study of nivolumab versus placebo in combination with neoadjuvant chemotherapy and adjuvant endocrine therapy in participants with high-risk, estrogen receptor-positive (er+), human epidermal growth factor receptor 2-negative (her2-) primary breast cancer (checkmate 7fl). ClinicalTrials.gov Identifier: NCT04109066. Updated March 12, 2024. Accessed October 24, 2024. https://clinicaltrials.gov/study/NCT04109066

14. Study of pembrolizumab (mk-3475) plus chemotherapy vs placebo plus chemotherapy as neoadjuvant therapy and pembrolizumab vs placebo as adjuvant therapy in participants with triple negative breast cancer (tnbc) (mk-3475-522/​keynote-522). ClinicalTrials.gov Identifier: NCT03036488. Updated July 12, 2024. Accessed October 24, 2024. https://clinicaltrials.gov/study/NCT03036488

15. Abemaciclib (ly2835219) plus fulvestrant compared to placebo plus fulvestrant in previously treated breast cancer (postmonarch). ClinicalTrials.gov Identifier: NCT05169567. Updated September 26, 2024. Accessed October 24, 2024. https://clinicaltrials.gov/study/NCT05169567

16. Study of pembrolizumab (mk-3475) plus chemotherapy vs placebo plus chemotherapy as neoadjuvant therapy and pembrolizumab vs placebo as adjuvant therapy in participants with triple negative breast cancer (tnbc) (mk-3475-522/​keynote-522). ClinicalTrials.gov Identifier: NCT03036488. Updated July 12, 2024. Accessed October 24, 2024. https://clinicaltrials.gov/study/NCT03036488

17. Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. February 26, 2020. doi: 10.1056/NEJMoa1910549

18. Trastuzumab deruxtecan (ds-8201a) versus investigator's choice for her2-low breast cancer that has spread or cannot be surgically removed [destiny-breast04]. ClinicalTrials.gov Identifier: NCT03734029. Updated April 11, 2024. Accessed October 24, 2024. https://clinicaltrials.gov/study/NCT03734029

19. Study of trastuzumab deruxtecan (t-dxd) vs investigator's choice chemotherapy in her2-low, hormone receptor positive, metastatic breast cancer (db-06). ClinicalTrials.gov Identifier: NCT04494425. Updated October 17, 2024. Accessed October 24, 2024. https://clinicaltrials.gov/study/NCT04494425?a=18