Studies presented at the 2023 San Antonio Breast Cancer Symposium (SABCS) significantly moved the needle forward in our treatment of breast cancer. We are increasingly learning how to stratify risk, so we can optimize therapy and minimize our patients’ exposure to treatments that will not be beneficial. Let’s look at how some of the most important presentations in San Antonio can help us do that.
De-escalation of Radiotherapy
In early-stage disease, we are beginning to optimize radiotherapy based upon the patient’s risk of recurrence. In San Antonio, we heard the results of two studies that affirm our ability to safely do so.
The IDEA trial addressed the question of whether tumor biology could be incorporated into decisions regarding the need for radiation after lumpectomy.1 The thought was that patients with a low recurrence score (≤ 18) on the Oncotype DX assay might fare well enough with endocrine therapy alone.
In a population of younger postmenopausal patients (aged 50–69), the omission of radiotherapy for patients with low recurrence scores who underwent 5 years of endocrine therapy did not compromise disease-free survival. Previous studies have shown that older postmenopausal patients with low–clinical risk tumors can potentially avoid radiation therapy. This latest finding allows us to consider a genomic-based approach for potentially avoiding radiation therapy in patients aged 50 to 60.
GUEST EDITOR
Jame Abraham, MD, FACP
We have eagerly awaited the results of the second study, NRG Oncology/NSABP B-51/RTOG 1304, which evaluated the omission of radiotherapy in patients who converted from lymph node–positive to –negative after neoadjuvant chemotherapy.2 There has been debate as to whether these newly node-negative patients should be treated as node-negative or treated according to their initial node-positive presentation.
For the irradiated group and the observation group, which did not receive radiotherapy, 5-year disease-free survival rates were the same, approximately 92% in each. Other clinical outcomes were also similar. Long-term follow-up, of course, will be important to ensure that omission of radiotherapy is not ultimately causing harm in patients with node-negative disease.
The results of these studies will allow us to have an evidence-based conversation with patients about the role of radiotherapy based upon their individual risk—such as genomic tests or response to neoadjuvant therapy.
Effectively Treating Brain Metastases
Data presented at SABCS 2023 clearly showed that tucatinib continues to be an effective agent for brain metastases, which we see in up to 30% of our patients with HER2-positive breast cancer. Given with capecitabine and trastuzumab, this highly selective small-molecule tyrosine kinase inhibitor established its progression-free and overall survival benefits in the previous HER2CLIMB study, including in patients with brain metastases.3
Now we have the results of the phase III HER2CLIMB-02 trial, which is a large trial prospectively designed to evaluate a novel combination treatment for patients with metastatic breast cancer, including those with brain metastases.4 Sara Hurvitz, MD, FACP, reported that median progression-free survival was 9.5 months with tucatinib plus adjuvant ado-trastuzumab emtansine (T-DM1) vs 7.4 months with T-DM1 alone, representing a 24% reduction in risk. Specifically, among the 40% of patients with brain metastases at baseline, median progression-free survival was 7.8 months vs 5.7 months, respectively—a 36% risk reduction.
The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend fam-trastuzumab deruxtecan-nxki (T-DXd) for the second-line treatment of metastatic HER2-positive disease and the HER2CLIMB regimen of tucatinib, trastuzumab, and capecitabine for the third line. But knowing the benefit of a tucatinib-containing regimen, I prefer the HER2CLIMB regimen for patients who have a substantial disease burden in the brain. Tucatinib and antibody-drug conjugates such as T-DXd are really changing the natural history of patients with brain metastases.
Targeting PIK3CA Mutations
The management of disease progression in patients with hormone receptor–positive metastatic disease is increasingly dependent on genomic drivers. One such driver is the PIK3CA mutation, which is seen in 30% to 40% of hormone receptor–positive, HER2-negative breast cancers. In May 2019, the PI3K inhibitor alpelisib was approved by the U.S. Food and Drug Administration based on the SOLAR and BYLieve trials,5,6 where the combination of alpelisib and fulvestrant improved outcomes over fulvestrant alone. But the use of this regimen in the clinic is challenging, as we see many side effects that impact the durability of treatment. Could we have a similar targeted agent with more mutant selectivity and better tolerability?
In San Antonio, we heard results of the phase III INAVO120 study,7 in which inavolisib, an investigational highly potent and selective PI3K inhibitor, was combined not only with fulvestrant but also with the CDK4/6 inhibitor palbociclib in previously untreated patients who had advanced disease with PIK3CA mutations. Since we now routinely combine endocrine therapy with a CDK4/6 inhibitor, the study evaluated a more contemporary regimen than previous studies of alpelisib.
The results seen with this unique agent were very impressive. The addition of inavolisib led to a statistically significant doubling in progression-free survival, from 7 months to 15 months, and a trend toward an overall survival benefit. The toxicity profile and low discontinuation rate were better than we have experienced with alpelisib, so adding this particular inhibitor to two standard drugs that are well tolerated should not be too challenging in the clinic. Pending the approval of inavolisib, potentially this triplet could be an option for patients with PIK3CA-mutated, hormone receptor–positive, HER2-negative advanced breast cancer.
Updates of Landmark Trials in Early Breast Cancer
The benefit of adjuvant T-DM1 was upheld by the long-term follow-up of the landmark KATHERINE trial, which has now shown a significant overall survival benefit in patients with HER2-positive early breast cancer with residual disease after neoadjuvant therapy.8 At the 8.4-year timepoint, 70% of patients treated with T-DM1 were alive, compared with 62% of the trastuzumab arm, reflecting a statistically significant 34% improvement in survival.
The findings bolster the 50% reduction in risk previously reported for disease-free survival9 and are reassuring regarding long-term safety. We now have even stronger data to support what has become the standard of care—adjuvant T-DM1—for HER2-positive patients who do not achieve a pathologic complete response.
Gabriel Hortobagyi, MD, FACP, presented long-term results of the NATALEE trial in hormone receptor–positive, HER2-negative early breast cancer, reporting continued improvement in invasive disease–free survival with the addition of the CDK4/6 inhibitor ribociclib to endocrine therapy.10 In this final analysis, with a median follow-up of almost 3 years, the 3-year invasive disease–free survival rate was 90.7% in the ribociclib arm vs 87.6% in the control arm, a 25% reduction in risk. Adjuvant ribociclib at 400 mg daily for 3 weeks on and 1 week off for 3 years could potentially be an option for patients with estrogen receptor–positive, HER2-negative stage II and III breast cancer.
Expanding the Potential for Immunotherapy
Progress in immunobiology led to the concept of enhancing host immunity to combat cancer. This has proven very successful in triple-negative breast cancer. In particular, checkpoint inhibition with pembrolizumab has achieved robust benefits in both the early and advanced disease settings for these challenging tumors. In San Antonio, Dr. Peter Schmid, MD, PhD, presented updated event-free survival from the phase III KEYNOTE-522 study, which evaluated neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab in triple-negative disease.11
At a median follow-up of 63 months, the 5-year event-free survival rate was 81.3% with pembrolizumab plus chemotherapy vs 72.3% with chemotherapy alone, a 37% reduction in risk. At 39 months of follow-up, the 3-year rate was 84.5% vs 76.8%, respectively. The benefit with pembrolizumab was generally consistent in key subgroups based on stage, nodal status, and T2 N0 status. Within the disease stage and nodal subsets, the reduction in events in the pembrolizumab arm was observed regardless of the achievement of pathologic complete response (although pathologic complete responders had the best outcomes, especially with pembrolizumab plus chemotherapy). These results further support pembrolizumab plus a platinum-containing neoadjuvant regimen followed by adjuvant pembrolizumab as the standard of care in patients with high-risk early triple-negative breast cancer.
We are learning that the benefit of checkpoint inhibition in breast cancer may not be limited to tumors that are the most immunogenic. It is promising to see an increase in pathologic complete responses in estrogen receptor–positive, HER2-negative tumors when they are treated with neoadjuvant pembrolizumab, as demonstrated in KEYNOTE-756.12 In patients with early-stage, high-risk, estrogen receptor–positive, HER2-negative breast cancer, pathologic complete responses were significantly improved—from 15.6% in the placebo arm to 24.3%, an 8.5% absolute difference—with a neoadjuvant regimen of pembrolizumab and weekly paclitaxel, followed by pembrolizumab plus anthracycline and cyclophosphamide, followed by surgery and adjuvant pembrolizumab plus endocrine therapy.
Joyce O’Shaughnessy, MD, presented subgroup analyses of KEYNOTE-756, reporting absolute improvements of 9.1% in stage II disease and 8.0% in stage III disease.12 A larger magnitude of benefit arose among node-positive patients, patients with higher levels of PD-L1 expression, and patients with estrogen receptor–low tumors (< 10% expression). These findings are very interesting—some of the first data we have seen in estrogen receptor–positive subsets—and they suggest we may be able to select patients most likely to benefit from immunotherapy. Obviously, longer follow-up will help to better delineate the benefit-vs-harm ratio of immune checkpoint inhibitors, which will ultimately dictate their optimal use in early breast cancer.
Exercise Imparts Benefits
Finally, we heard more evidence in support of regular exercise—this time as part of palliative care. The randomized prospective PREFERABLE-EFFECT study found that patients who participated in a supervised, high-intensity exercise program for 9 months experienced an improvement in physical function, physical fitness, fatigue, pain, dyspnea and quality of life.13 This study adds to a wealth of data showing the undeniable benefits of exercise in persons with cancer, and we need to put more effort into creating programs that will facilitate this.
DISCLOSURE: Dr. Abraham has received research funding from Daiichi Sankyo/AstraZeneca, Pfizer, and Seattle Genetics.
REFERENCES
1. Jagsi R, Griffith K, Harris E, et al: Five-year outcomes of the IDEA trial of endocrine therapy without radiotherapy after breast-conserving surgery for postmenopausal patients age 50–69 with genomically selected favorable stage I breast cancer. 2023 San Antonio Breast Cancer Symposium. Abstract GS02-08. Presented December 7, 2023.
2. Mamounas E, Bandos H, White J, et al: Loco-regional irradiation in patients with biopsy-proven axillary node involvement at presentation who become pathologically node-negative after neoadjuvant chemotherapy: Primary outcomes of NRG Oncology/NSABP B-51/RTOG 1304. 2023 San Antonio Breast Cancer Symposium. Abstract GS02-07. Presented December 7, 2023.
3. Murthy RK, Loi S, Okines A, et al: Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med 382:597-609, 2020.
4. Hurvitz S, Loi S, O’Shaughnessy J, et al: HER2CLIMB-02: Randomized, double-blind, phase 3 trial of tucatinib and trastuzumab emtansine for previously treated HER2-positive metastatic breast cancer. 2023 San Antonio Breast Cancer Symposium. Abstract GS01-10. Presented December 6, 2023.
5. André F, Ciruelos EM, Juric D, et al: Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: Final overall survival results from SOLAR-1. Ann Oncol 32:208-217, 2021.
6. Rugo HS, Lerebours F, Ciruelos E, et al: Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): One cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol 22:489-498, 2021.
7. Jhaveri K, Seock-Ah I, Saura C, et al: Phase III study of inavolisib or placebo in combination with palbociclib and fulvestrant in patients with PIK3CA-mutant, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer: INAVO120 primary analysis. 2023 San Antonio Breast Cancer Symposium. Abstract GS03-13. Presented December 8, 2023.
8. Loibl S, Mano M, Untch M, et al: Phase III study of adjuvant ado-trastuzumab emtansine vs trastuzumab for residual invasive HER2-positive early breast cancer after neoadjuvant chemotherapy and HER2-targeted therapy: KATHERINE final IDFS and updated OS analysis. 2023 San Antonio Breast Cancer Symposium. Abstract GS03-12. Presented December 8, 2023.
9. von Minckwitz G, Huang CS, Mano MS, et al: Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med 380:617-628, 2019.
10. Hortobagyi G, Stroyakovsky D, Yardley D, et al: Ribociclib + nonsteroidal aromatase inhibitor as adjuvant treatment in patients with HR+/HER2− early breast cancer: Final invasive disease–free survival analysis from the NATALEE trial. 2023 San Antonio Breast Cancer Symposium. Abstract GS03-03. Presented December 8, 2023.
11. Schmid P, Cortes J, Dent R, et al: Neoadjuvant pembrolizumab or placebo plus chemotherapy followed by adjuvant pembrolizumab or placebo for early-stage triple-negative breast cancer: Updated event-free survival results from the phase 3 KEYNOTE-522 study. 2023 San Antonio Breast Cancer Symposium. Abstract LBO1-01. Presented December 5, 2023.
12. Cardoso F, O’Shaughnessy J, McArthur H, et al: Phase 3 study of neoadjuvant pembrolizumab or placebo plus chemotherapy, followed by adjuvant pembrolizumab or placebo plus endocrine therapy for early-stage high-risk ER+/HER2– breast cancer: KEYNOTE-756. 2023 San Antonio Breast Cancer Symposium. Abstract GS01-02. Presented December 6, 2023.
13. May A, Hiensch A, Depenbusch J, et al: Effects of a structured and individualized exercise program on fatigue and health-related quality of life in patients with metastatic breast cancer: The multinational randomized controlled PREFERABLE-EFFECT study. 2023 San Antonio Breast Cancer Symposium. Abstract GS02-10. Presented December 7, 2023.
