An era of advanced molecular testing and personalized medicine has allowed for the de-escalation of breast cancer treatment for many patients. This is part 1 of a 2-part series on overtreatment of breast cancer.
As we celebrate advancements in breast cancer treatment, it is important to examine whether we could achieve the same excellent results with less toxicity. Concerns about overtreating breast cancer patients have led our team at Baptist Health Miami Cancer Institute to focus on safely de-escalating treatment, when appropriate, and finding the right balance between effective therapy and unnecessary toxicity.
Overtreatment is a complex issue, and it is often difficult to determine whether it may have occurred. If a patient's cancer does not recur, we consider the treatment successful. However, we sometimes wonder if we could have achieved that same outcome with less-intensive therapy. To address this, results from de-escalation trials are helping us deliver the right amount of treatment for each patient.
De-escalation has been particularly successful in early-stage hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer. In the past, most patients with this type of breast cancer were considered for chemotherapy. However, with the advent of genomic assays such as Oncotype DX and MammaPrint, we can now identify patients who can safely forgo chemotherapy. This personalized approach allows us to spare selected patients from unnecessary toxicity while still achieving positive outcomes.
The 21-gene Oncotype DX assay has been validated in both the TAILORx trial (NCT00310180) for node negative patients with HR+/HER2- breast cancer and in the RXPonder trial for patients with HR+/HER2- breast cancer and 1-3 positive lymph nodes.1 TAILORx was a phase 3 randomized controlled trial of 6711 women with recurrence scores (RS) of 11-25 who were randomized to chemotherapy and endocrine therapy vs endocrine therapy alone.
In the intent to treat population, endocrine therapy alone was non-inferior to chemoendocrine therapy in terms of invasive disease-free survival (iDFS) with a hazard ratio (HR) of 1.08 (95% confidence interval [CI], 0.94 to 1.24; P =.26) at final analysis. The 9-year IDFS was 83.3% for endocrine therapy alone vs 84.3% for the chemoendocrine group. Distant recurrence-free survival and overall survival were also non-inferior among the endocrine therapy alone group. There was a benefit for the addition of chemotherapy in a subset of patients under age 50 in the TAILORx trial with RS 16-25, which will be discussed in detail later.
Similar results were noted in the RxPONDER trial (NCT01272037), where patients with 1-3 positive lymph nodes and a RS of 25 or less were randomized to chemoendocrine therapy vs endocrine therapy alone.2 Post-menopausal women had no benefit from chemotherapy with 5-year iDFS of 91.3% in the chemoendocrine group and 91.9% in the endocrine therapy alone group. As a result, post-menopausal patients with HR+/HER2- breast cancer which is T1-T2 with 3 or fewer positive lymph nodes and a RS of 25 or less can safely omit chemotherapy.
The MINDACT trial (NCT00433589)evaluated the MammaPrint 70 gene signature in patients with HR+/HER2- breast cancer with up to three positive lymph nodes. Patients were assessed for their clinical risk based on traditional clinico-pathologic features and their genomic risk based on the MammaPrint assay.3
Patients who were clinically high risk and genomically low risk were randomized to receive chemoendocrine therapy vs endocrine therapy alone. Investigators were looking to see whether a genomically low-risk MammaPrint result in a clinically high-risk patient could reliably predict a lack of benefit from chemotherapy. Updated analysis shows that among women over age 50 with HR+/HER2- breast cancer with up to 3 positive lymph nodes, clinical high risk, and genomic low risk, 8-year distant metastasis free survival was 90.2% with chemoendocrine therapy vs 90.0% in endocrine therapy alone.
These results mirror those seen with the Oncotype DX assay, and either of these genomic assays can be used to effectively select women who can omit chemotherapy.
Overtreatment also occurs when we use medications with higher toxicity as opposed to less toxic but equally efficacious alternatives. For example, in high-risk HR+/HER2- breast cancer patients, anthracyclines have traditionally been a component of the chemotherapy regimen. However, the joint analysis of the ABC trials showed that there is no benefit from the addition of anthracycline for lymph node-negative patients with HR+/HER2- breast cancer, reducing the risk of long-term toxicities.4 In this analysis of 3 adjuvant trials, over 4,000 patients with early-stage breast cancer were randomly assigned to docetaxel and cytoxan (TC) x6 vs an anthracycline and taxane-containing regimen (TaxAC). The investigators concluded that anthracycline improved iDFS for the intent to treat population, but an exploratory analysis showed that these benefits were restricted to HR- patients or those with node-positive HR+ disease. For node-negative HR+ breast cancer, 4-year iDFS was 91.5% for TaxAC and 94.2% for TC (HR, 0.69; 95% CI 0.39-1.19). Based on these results, we tend to use TC in patients with node-negative HR+/HER2- breast cancer with a high-risk result on a genomic assay such as Oncotype DX or MammaPrint.
Duration of endocrine therapy has been an extensively studied and intensely debated topic among breast cancer experts. Many patients have become quite comfortable taking daily endocrine therapy and may even experience anxiety when stopping therapy. Because some of the most concerning toxicities of this treatment can be silent, such as loss of bone density and cardiovascular effects, it is important to ensure we are only extending duration of adjuvant endocrine therapy in those who will benefit.
Multiple trials have shown a modest benefit from extending adjuvant endocrine therapy beyond five years, but we know that the benefits do not apply to all patients. The Breast Cancer Index (BCI) assay is an especially useful tool in patients who are approaching five years of endocrine therapy, have no signs of recurrence, and would be willing to extend the duration of their therapy beyond 5 years. Across multiple extended adjuvant endocrine therapy trials, such as MA.17, NSABP B-42, and the IDEAL trial (BOOG 2006-05; Eudra-CT 2006-003958-16), BCI consistently identified patients who will benefit from extended therapy.5
While we tend to offer extended endocrine therapy to those with higher-risk features such as node positivity, in lower-risk patients BCI can guide our recommendations on the duration of endocrine therapy and also help patients feel comfortable with discontinuation once appropriate.
Proof of Concept
Another area where de-escalation has been particularly successful is with respect to HER2+ breast cancer. Traditionally viewed as an aggressive disease with inferior outcomes, recent studies have challenged this notion.
The single-arm phase II APT study (NCT00542451) evaluated a de-escalated regimen of weekly paclitaxel for 12 weeks in addition to trastuzumab for one year in patients with small node-negative HER2+ breast cancer.6 Recent final analysis published by Tolaney et al (Lancet Oncology 2023) showed an impressive 96.3% 10-year recurrence-free survival and 91.3% 10-year IDFS. Based on earlier results from this trial, the APT regimen of trastuzumab and paclitaxel (TH) has become the standard of care for patients who qualify.
However, the use of paclitaxel can sometimes lead to permanent neuropathy and many patients feel strongly about avoiding alopecia. To address this, the ATEMPT trial (NCT01853748) explored the use of trastuzumab emtansine (T-DM1) as a less toxic alternative for the treatment of stage 1 HER2+ breast cancer.7 The primary outcome was clinically relevant toxicity (CRT), which was found to be similar between those receiving T-DM1 (CRT 46%) and those receiving TH (CRT 47%; P =.83). While the trial reported similar overall toxicity, analysis of patient reported outcomes showed that T-DM1 caused less neuropathy, less alopecia, and resulted in better work productivity compared to TH. The three-year iDFS for T-DM1 was 97.8%, and although the trial was not powered to detect differences in efficacy between the two arms, this compares favorably with historical IDFS for TH.
So, although the trial was referred to as a “negative trial” because it failed to prove T-DM1 to be less toxic than TH, it has strengthened our interest in de-escalation for stage 1 HER2+ breast cancer. The ATEMPT 2.0 trial is now underway in a similar population of patients using six cycles of T-DM1 followed by subcutaneous trastuzumab to complete one year vs TH to achieve the same excellent outcomes with less toxicity.8
While de-escalation is especially important when appropriate, we also need to recognize when current therapy is insufficient and offer escalated treatment in such cases.
Pathologic complete response (pCR) is a valuable biomarker to assess response to neoadjuvant therapy for breast cancer and to tailor treatment in the adjuvant setting for both HER2+ and triple negative breast cancer (TNBC) patients.
In HER2+ breast cancer, patients who achieve pCR after neoadjuvant therapy can continue their anti-HER2 therapy to complete one year. Those who do not achieve pCR should be offered escalated therapy with T-DM1 per the KATHERINE trial (NCT01772472)9 or clinical trial such as COMPASS HER2 RD (NCT04457596)10 or DESTINY-Breast05 (NCT04622319).11
Similarly, in patients with TNBC receiving pembrolizumab plus chemotherapy per the KEYNOTE-522 trial (NCT03036488), patients who achieve pCR enjoy an excellent 3-year event-free survival by continuing pembrolizumab alone to complete 1 year.12 Trials evaluating whether pembrolizumab can be discontinued in those who achieve pCR are also underway as a means of de-escalation. If pCR is not achieved with the KEYNOTE-522 regimen, most experts believe an additional treatment should be added for this high-risk group of TNBC patients. Capecitabine can be added to pembrolizumab for BRCA wild-type patients, following data from the CREATE-X trial that were published prior to KEYNOTE-522, understanding that adjuvant capecitabine was not allowed on the Keynote-522 trial.
Olaparib can be added to pembrolizumab for those with germline BRCA mutations. While these combinations have not been studied for efficacy in this setting, their safety has been demonstrated in other trials and their efficacy has been proven individually. There are a number of promising clinical trials for patients with TNBC who do not achieve pCR, and we should be mindful to refer these patients who are at increased risk of relapse to participate in such trials.
It is crucial to engage in shared decision-making with patients to decide on the intensity of treatment. Patients should be informed about the data and involved in the physician’s thought process. In cases where uncertainty exists, it is important to align the treatment approach with the patient's philosophy and goals.
Physicians may tend toward overtreatment due to the fear of recurrence and the desire to exhaust all treatment options. However, in the era of personalized medicine, tailoring the right therapy for each patient is essential. By identifying patients who will not benefit from certain treatments, we can spare them toxicity.
Planning for the long-term health and well-being of early breast cancer patients is particularly important given that we expect the majority to enjoy significant longevity. Ensuring that only those who truly need aggressive treatment receive it is of the utmost importance. By de-escalating treatment and personalizing therapy, we can achieve excellent outcomes while minimizing toxicity.
Naomi Dempsey, MD, is a board-certified medical oncologist at Baptist Health Miami Cancer Institute, specializing in breast cancer medical oncology. Dr. Dempsey is a member of the American Society of Clinical Oncology and the American College of Physicians. She practices at Baptist Health’s Wellness & Medical Complex in Plantation, Florida.
1. 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.
2. Kalinsky K, Barlow WE, Gralow JR, et al. 21-Gene assay to inform chemotherapy benefit in node-positive breast cancer. N Engl J Med. 2021;385(25):2336-2347. doi: 10.1056/NEJMoa2108873
3. Piccart M, Veer LJ, Poncet C, et al. 70-gene signature as an aid for treatment decisions in early breast cancer: updated results of the phase 3 randomised MINDACT trial with an exploratory analysis by age. Lancet Oncol. 2021;22(4):476-488. doi: 10.1016/S1470-2045(21)00007-3
4. Blum JL, Flynn PJ, Yothers G, et al. Anthracyclines in early breast cancer: The ABC trials—USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017;35(23): 2647–2655. doi: 10.1200/JCO.2016.71.4147
5. Blok EJ, Kroep JR, Kranenbarg EM, Carpentier MD, et al. Optimal duration of extended adjuvant endocrine therapy for early breast cancer; Results of the IDEAL Trial (BOOG 2006-05). J Natl Cancer Inst. 2018;110(1):40-48. doi: 10.1093/jnci/djx134
6. Tolaney SM, Taratino P, Graham N, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer: final 10-year analysis of the open-label, single-arm, phase 2 APT trial. Lancet. 2023;24(3):273-285. doi: 10.1016/S1470-2045(23)00051-7
7. Tolaney SM, Tayob N, Dnag C, et al. Adjuvant trastuzumab emtansine versus paclitaxel in combination with trastuzumab for stage i her2-positive breast Cancer (ATEMPT): A randomized clinical trial. J Clin Oncol. 2021;39(21):2375-2385. doi: 10.1200/JCO.20.03398
8. ATEMPT 2.0: Adjuvant T-DM1 vs TH. ClinicalTrials.gov. Updated March 13, 2023. Accessed August 9, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04893109
9. Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382(9):810-821. doi: 10.1056/NEJMoa1910549
10. T-DM1 and tucatinib compared with T-DM1 alone in preventing relapses in people with high risk HER2-positive breast cancer, the CompassHER2 RD trial. ClinicalTrials.gov. Updated March 10, 2023. Accessed August 9, 2023.
11. A study of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in high-risk HER2-positive participants with residual invasive breast cancer following neoadjuvant therapy (DESTINY-Breast05). ClinicalTrials.gov. Updated August 2, 2023. Accessed August 9, 2023.
12. Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 202;382(9):810-821. doi: 10.1056/NEJMoa1910549