De-Escalation Strategies, Biomarkers Could Refine Treatment Algorithm for Early-Stage HER2+ Breast Cancer

Sara M. Tolaney, MD, MPH

Although adjuvant treatment regimens, such as ado-trastuzumab emtansine (T-DM1; Kadcyla) or trastuzumab (Herceptin) plus paclitaxel, have improved outcomes for patients with HER2-positive, early-stage breast cancer, developing more personalized treatment approaches in this setting could help spare certain patients from unnecessary toxicity or determine which patients require escalated or de-escalated therapy, according to Sara M. Tolaney, MD, MPH.

“When thinking about how we further tailor therapy in this era...I have taken the approach that we need to think about using less [treatment] or less-toxic therapy in patients we can select for better outcomes,” Tolaney said during a presentation at the 23rd Annual International Congress on the Future of Breast Cancer^® East.¹

In her presentation, Tolaney outlined de-escalated and less-toxic treatment approaches for patients with early-stage HER2-positive breast cancer; detailed how a pathological complete response (pCR) to neoadjuvant therapy could inform personalized treatment approaches; and highlighted the role of biomarkers in individualizing care plans.

Tolaney is a senior physician, chief of the Division of Breast Oncology, and associate director of the Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute, and an associate professor of medicine at Harvard Medical School in Boston, Massachusetts.

Exploring De-escalated, Better-Tolerated Treatment Options

Tolaney explained that data have demonstrated that less therapy could still provide similar outcomes for patients with stage I HER2-positive breast cancer. Specifically, she highlighted the abbreviated use of chemotherapy, shorter durations of trastuzumab, and the omission of anthracyclines from chemotherapy regimens as areas of opportunity.

“Trastuzumab has changed the natural history of HER2-positive breast cancer, where it was once thought to be the subtype of breast cancer associated with the worst outcomes,” Tolaney said. “Now, it is [potentially] heading toward the best outcomes—at least the outcomes [of these patients] do seem on par with [those who have] HER2-negative disease.”

Despite the improved outcomes in the early-stage setting for patients with HER2-positive breast cancer, Tolaney noted that approximately 15% to 20% of this population will still experience disease recurrence, underscoring the need to further improve treatment approaches.

Tolaney highlighted 10-year follow-up data from the phase 2 APT trial (NCT00542451), which showed that patients with HER2-positive, estrogen receptor–positive or –negative, node-negative breast cancer whose tumors were no more than 3 cm in size (n = 406), experienced a 10-year invasive disease-free survival (iDFS) rate of 91.3% (95% CI, 88.3%-94.4%). However, Tolaney cautioned about end point selection in early-stage breast cancer trials. Notably, during APT, only 6 distant metastases events occurred, and the 10-year recurrence-free interval (RFI) rate—comprised of locoregional recurrence, distant recurrence, and any death from breast cancer—was 96.3% (95% CI, 94.3%-98.3%).²

“In general, if someone has stage I [HER2-positive] disease, giving trastuzumab plus paclitaxel results in good outcomes,” Tolaney said. “However, there are probably a lot of patients who don’t need any treatment, and there may be a few patients who could need more.”

She further explained that results from APT showed that de-escalation trials can be practice-changing only if there are very few recurrences. Additionally, studies like this cannot identify patients who do not need systemic therapy, and end point selection in trials with low expected event rates are crucial, making recurrence-free interval (RFI) a reasonable end point for de-escalation studies.

The phase 2 ATEMPT trial (NCT01853748) investigated the potential role for T-DM1 in patients with stage I HER2-positive breast cancer, where enrolled patients were randomly assigned 3:1 to receive T-DM1 (n = 383) or trastuzumab plus paclitaxel (n = 114). Notably, the study was not powered to compare efficacy between the 2 arms, although investigators did examine differences in clinically relevant toxicities (CRTs) between the regimens.³

Data showed the 5-year iDFS and RFI rates in the T-DM1 arm were 97.0% (95% CI, 95.2%-98.7%) and 98.3% (95% CI, 97.0%-99.7%), respectively. Tolaney explained that there was not a difference in the incidence of CRTs between the 2 arms; however, differences in the types of adverse effects were observed. Notably, patients treated with trastuzumab plus paclitaxel experienced a higher rate of grade 2 or higher neurotoxicity vs T-DM1 (23% vs 11%). T-DM1 was associated with a higher rate of toxicity leading to early discontinuation vs trastuzumab plus paclitaxel (17% vs 6%).

Despite no differences observed in CRTs, patient-reported outcomes (PROs) favored T-DM1. Patients in the trastuzumab plus paclitaxel arm reported a decline in quality of life (QOL) during the first 3 months of treatment, and QOL for patients treated with T-DM1 was higher for the duration of the study.

“One lesson learned [from ATEMPT] is that you can’t measure everything by these end points. PROs are critical to understanding how patients are tolerating therapy,” Tolaney said. “When we asked patients [in ATEMPT] about QOL, these measures were much better in the T-DM1 arm compared with trastuzumab plus paclitaxel. [Patients also] don’t lose their hair with T-DM1, which makes a big difference to patients as well.”

Regarding the potential de-escalation of trastuzumab in patients with stage I disease, Tolaney noted that 1 year of adjuvant treatment remains the SOC. She said that additional work is needed to see whether a shorter duration of treatment would not diminish efficacy in this patient population. The ongoing phase 2 ATEMPT 2.0 trial (NCT04893109) is evaluating 6 cycles of T-DM1, followed by 11 cycles of trastuzumab, vs SOC trastuzumab plus paclitaxel, as adjuvant therapy for patients with stage I, HER2-positive breast cancer.

The ongoing phase 2 STOP-HER2 trial (NCT05721248) is randomly assigning patients with HER2-positive early-stage breast cancer who achieved pCR following neoadjuvant chemotherapy plus HER2-directed therapy to receive 1 year of adjuvant treatment with trastuzumab with or without pertuzumab (Perjeta), or 6 months of adjuvant trastuzumab with or without pertuzumab.

Tolaney highlighted one area of treatment de-escalation already explored in the early-stage, HER2-positive setting: the omission of anthracyclines. She spotlighted data from the phase 3 BCIRG006 (NCT00021255) and TRAIN-2 (NCT01996267) trials, which showed that similar outcomes can be achieved with taxane-based therapy vs anthracycline-based therapy, including in patients with high-risk, node-positive disease.

"I've stopped utilizing anthracyclines in HER2-positive disease. We see less cardiac toxicity, less secondary leukemias, and I don't think [anthracyclines] are improving outcomes," Tolaney said.

Using pCR to Inform Treatment Approaches

Tolaney explained that the continued goal in the early-stage HER2-positive breast cancer space is to use response to neoadjuvant therapy as a guide for further treatment decisions. She spotlighted data from the phase 3 KATHERINE trial (NCT01772472), which evaluated adjuvant T-DM1 vs trastuzumab in patients who had residual invasive tumors in the breast or axillary nodes.

In the final analysis of the trial, which had a median follow-up of 8.4 years, T-DM1 (n = 743) led to a 46% reduction in the risk of an iDFS event vs trastuzumab (n = 743; HR, 0.54; 95% CI, 0.44-0.66; P < .0001). The 7-year iDFS rates were 80.8% for T-DM1 vs 67.1% for trastuzumab.⁴

Despite the data from KATHERINE, Tolaney said there remains a need to continue improving outcomes. Notably, patients in KATHERINE who had node-positive disease were at a higher risk of recurrence, and there was a lack of improvement in central nervous system recurrence with T-DM1.

“In my mind, it is very critical to give all patients with stage II or III disease preoperative therapy so that you can tailor [adjuvant] therapy because it is impacting survival outcomes,” Tolaney said. “Although [KATHERINE] has been a pivotal, practice-changing study, there are still questions that remain.”

The COMPASSHER2 trials, comprised of the phase 2 CompassHER2-pCR study (NCT04266249) and the phase 3 CompassHER2 RD study (NCT04457596), are treating patients based on pCR status following neoadjuvant therapy and surgery. Those with a pCR are enrolled to CompassHER2-pCR to receive 1 year of trastuzumab plus pertuzumab, with radiation and endocrine therapy given if appropriate. Those without a pCR are proceeding to CompassHER2 RD, where they are being randomly assigned to T-DM1 or T-DM1 plus tucatinib (Tukysa).

Fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) is also being investigated as adjuvant therapy in the phase 3 DESTINY-Breast05 trial (NCT04622319). Patients with early-stage HER2-positive breast cancer who have residual disease following neoadjuvant chemotherapy and HER2-directed therapy are being randomly assigned to T-DXd or T-DM1.

Tolaney also pointed to neratinib (Nerlynx) as a possible escalation option in the adjuvant setting. She explained benefits have been observed in patients with high-risk, hormone receptor–positive, HER2-positive disease who have residual disease after preoperative therapy. She cautioned that the phase 3 EXTENET trial (NCT00878709), which evaluated 1 year of neratinib vs placebo in patients who received prior adjuvant trastuzumab, was conducted prior to the integration of adjuvant pertuzumab and T-DM1 into the SOC. Neratinib has also been associated with grade 3/4 diarrhea in approximately 40% of patients, and Tolaney emphasized the need for prophylactic treatment or a dose-escalation approach with neratinib.

“I typically will only think about [using neratinib] in someone who has high-risk, residual, hormone receptor–positive, [HER2-positive] disease."

Emerging Biomarkers in Early-Stage HER2-Positive Breast Cancer

Beyond using pCR as a guide for treatment decisions, other biomarkers could help tailor up-front therapy, Tolaney said. The HER2DX genomic test is designed to evaluate 27 genes and 4 gene signatures: immune/B-cell, proliferation, luminal differentiation, and HER2 amplicon expression. By analyzing these genes, the test provides a relapse risk score, a pCR likelihood score, and an ERBB2 mRNA score.

“HER2DX is one assay that has some promise because it will give you the risk of having a recurrence or the [potential] of achieving a pCR with a particular treatment,” she said. “It is an assay that is getting further validated. There have been lots of trials where it’s been tested, and the meta-analysis that was done did show that it was able to separate outcomes based on the risk score, which has been quite promising.”

Tolaney painted a scenario where HER2DX could be utilized to determine up-front treatment. If a patient had a medium potential of achieving a pCR, she said a multi-agent chemotherapy regimen could be considered. Conversely, if a patient had a high probability of experiencing a pCR, it could be possible to use 1 chemotherapy agent plus dual HER2-targeted therapy in the neoadjuvant setting, she said.

Tolaney concluded by highlighting her current view of the treatment algorithm for patients with early-stage HER2-positive breast cancer. In patients with T≤1 cm and cN0 disease, she will proceed directly to surgery, followed by adjuvant trastuzumab plus paclitaxel for those with stage I disease or docetaxel plus carboplatin and trastuzumab with or without pertuzumab for those with stage II or III disease. If patients present with T>1 cm and ≤2 cm disease, she will conduct an axillary ultrasound to determine whether neoadjuvant therapy is necessary. In those with T>2 cm and/or node-positive disease, the SOC is neoadjuvant docetaxel plus carboplatin, trastuzumab, and pertuzumab, followed by adjuvant trastuzumab plus pertuzumab in patients who achieve a pCR, or adjuvant T-DM1 in those with residual disease.

"If [patients] have node-positive or larger [tumors], they need preoperative treatment, and then you can adjust [adjuvant therapy] based on response at the time of surgery,” Tolaney concluded.

References

1. Tolaney SM. New insights into optimizing HER2-directed therapy in the curative setting. Presented at: 23rd Annual International Congress on the Future of Breast Cancer East; July 19-20, 2024; New York, NY.
2. Tolaney SM, Tarantino 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 Oncol. 2023;24(3):273-285. doi:10.1016/S1470-2045(23)00051-7
3. Tolaney SM, Hu J, Dang C, et al. A randomized phase II study of adjuvant trastuzumab emtansine (T-DM1) vs paclitaxel (T) in combination with trastuzumab (H) for stage I HER2-positive breast cancer (BC) (ATEMPT). Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS1-05.
4. 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. Presented at: 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX. Abstract GS03-12