Dr Waks on Ongoing Research in Residual HER2+ Breast Cancer

Adrienne G. Waks, MD, associate director, Breast Oncology Clinical Research, Dana-Farber Cancer Institute; associate professor, medicine, Harvard Medical School, discusses the adjuvant standard of care (SOC) used to lower the risk of disease recurrence in patients with HER2-positive breast cancer who have residual disease, as well as ongoing research investigating ways to improve standard treatment outcomes in this population.

The current SOC for reducing recurrence risk in this population is ado-trastuzumab emtansine (T-DM1; Kadcyla), which elicited an overall survival (OS) advantage compared with trastuzumab (Herceptin) in the phase 3 KATHERINE trial (NCT01772472), Waks begins. In KATHERINE, T-DM1 was associated with OS benefits in patients with minimal residual disease or those whose residual disease had converted to HER2-negative disease at the time of surgery.

Two ongoing clinical trials are exploring potential enhancements to the efficacy of T-DM1, Waks says. The phase 3 CompassHER2 RD trial (NCT04457596) is evaluating the addition of tucatinib, a HER2-directed TKI, to T-DM1 in patients with residual HER2-positive invasive breast cancer after neoadjuvant therapy. If this trial is successful, this regimen could become a new SOC for certain patients, particularly because dual HER2 blockade has proven more effective than single-agent HER2 blockade in select populations, Waks notes. Furthermore, tucatinib’s activity in the central nervous system (CNS) is particularly promising, she says. This could address a limitation observed in the KATHERINE trial, where T-DM1 did not significantly reduce CNS recurrences despite reducing overall recurrences, Waks explains.

The second trial is the phase 3 DESTINY-Breast05 trial (NCT04622319), which is comparing T-DM1 with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in patients with high-risk, HER2-positive residual invasive breast cancer following neoadjuvant therapy. T-DXd’s performance is superior to that of T-DM1 in the metastatic setting, raising the possibility that it could also outperform T-DM1 in the residual disease setting, Waks emphasizes. Although the results from DESTINY-Breast05 are not yet available, its outcomes may alter the SOC for patients with HER2-positive breast cancer.

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Adrienne G. Waks, MD, discusses efforts to improve treatment outcomes for patients with HER2-positive breast cancer with residual disease.

Dr Waks on Anthracycline- vs Taxane-Based Therapy in HER2+ Breast Cancer

Adrienne G. Waks, MD, physician, associate director, Breast Oncology Clinical Research, Dana-Farber Cancer Institute, assistant professor, medicine, Harvard Medical School, discusses 

anthracycline- and taxane-based regimens compare with one another

 as neoadjuvant and adjuvant treatment options for patients with HER2-positive breast cancer.

When comparing anthracycline- and taxane-based regimens as neoadjuvant treatment options for patients with HER2-positive breast cancer, it’s crucial to consider the differences in toxicity, Waks begins. Anthracycline-based regimens, especially when combined with HER2-targeted agents, are associated with a higher risk of cardiotoxicity, according to Waks. Additionally, there is a slightly increased risk of secondary leukemias associated with anthracycline-containing regimens, she explains. These differences in toxicity profiles are significant and have been well documented across various studies, Waks notes.

Regarding efficacy, current data indicate that anthracycline- and taxane-based regimens provide comparable long-term protection against recurrence in HER2-positive breast cancer, she continues. However, it’s important to note that the existing studies were not specifically designed or powered to directly compare long-term outcomes between anthracycline and non-anthracycline chemotherapy backbones, Waks notes. Although the available data are reassuring in terms of efficacy, they are not definitive for long-term outcomes, she reports.

Given the established differences in toxicity and the lack of conclusive data favoring one regimen over the other in terms of long-term efficacy, the current standard of care for most patients with HER2-positive breast cancer involves omitting anthracyclines in both the neoadjuvant and adjuvant settings, Waks states. This treatment approach minimizes the risk of cardiotoxicity and other potential adverse effects and still provides effective treatment for HER2-positive breast cancer, Waks says. In summary, the decision to omit anthracyclines is supported by both the toxicity profile and the reassuring, albeit not definitive, data on long-term outcomes, making it the preferred choice for most patients, she concludes.

Adrienne G. Waks, MD, discusses how neoadjuvant and adjuvant anthracycline- and taxane-based regimens compare with one another in HER2+ breast cancer.

Adrienne G. Waks, MD, discusses implications of the potential use of first-line T-DXd in HER2-positive breast cancer.

Dr Waks on Key Questions Regarding the First-Line Use of T-DXd in HER2+ Breast Cancer

Adrienne G. Waks, MD, physician, associate director of Clinical Research, Dana-Farber Cancer Institute, instructor in medicine, Harvard Medical School, discusses key questions and potential implications for replacing the prior first-line standard of care (SOC) with fam-trastuzumab-deruxtecan-nxki (T-DXd) in HER2-positive breast cancer.

An important question in treating HER2-positive metastatic breast cancer is whether the frontline standard of care will shift from the CLEOPATRA regimen (NCT00567190) to T-DXd, depending on the results of the ongoing phase 3 DESTINY-Breast09 trial (NCT04784715), Waks begins. The CLEOPATRA regimen, which combines pertuzumab (Perjeta) with trastuzumab (Herceptin) and chemotherapy, typically involves 4 to 6 months of treatment with chemotherapy, followed by maintenance with HER2-directed therapy alone, she says. This approach significantly reduces toxicity and improves the quality of life for patients, allowing them to experience durable benefits and lead relatively normal lives with minimal adverse effects (AEs), Waks reports.

The DESTINY-Breast09 trial is assessing the upfront use of T-DXd alone or in combination with pertuzumab plus trastuzumab vs a taxane plus pertuzumab and trastuzumab in metastatic disease. If the DESTINY-Breast09 trial demonstrates positive results and T-DXd is moved into the front line, it will introduce a new treatment paradigm, she emphasizes. Currently, the treatment protocol in DESTINY-Breast09 involves continuing T-DXd until disease progression or unacceptable adverse events, which differs significantly from the dosing schedule for the CLEOPATRA regimen. Although T-DXd is highly effective, it is also associated with considerable toxicity, Waks elucidates. This raises concerns about the long-term sustainability of maintaining patients on such a regimen indefinitely, as patients may experience extended periods on a potentially toxic therapy, she adds

The key question that will emerge is how to optimize the use of T-DXd in the first-line setting to balance efficacy and quality of life, Waks continues. One potential strategy could involve an induction phase with T-DXd, followed by a maintenance phase with trastuzumab and pertuzumab. This approach would necessitate comprehensive studies to gather efficacy, safety, feasibility, and patient-reported outcome data to determine the best course of action, she states.

Research will also need to focus on the optimal duration of T-DXd therapy before transitioning to maintenance therapy, Waks expands. This would involve assessing how many cycles of T-DXd are necessary to achieve maximum benefit before switching to a less toxic regimen. Additionally, understanding the long-term effects of continuous T-DXd therapy on patients’ health and quality of life will be crucial, Waks concludes.

drienne G. Waks, MD, discusses efforts to address unmet needs in HER2-positive breast cancer.  

Dr Waks on Unmet Clinical Needs in Patients With HER2+ Breast Cancer

Adrienne G. Waks, MD, physician, associate director of Clinical Research, Dana-Farber Cancer Institute, instructor in medicine, Harvard Medical School, discusses the need for more personalized approaches in the treatment of patients with HER2-positive breast cancer.

, Waks and colleagues presented data on the prevalence and dynamics of circulating tumor DNA (ctDNA) in patients with stage II and III HER2-positive breast cancer from the single arm, phase 2 DAPHNe trial (NCT03716180). In DAPHNe, patients were treated with a combination of neoadjuvant paclitaxel, trastuzumab (Herceptin) and pertuzumab (Perjeta), Waks details.

In the context of early-stage HER2-positive breast cancer, there is a significant unmet need for more personalized approaches to treatment, Waks states. Currently, physicians can choose to administer extensive chemotherapy and multiple HER2-targeted drugs; on the other hand, they can opt for minimal chemotherapy or solely HER2-targeted therapies depending on individual and disease factors, she states. Although the arsenal of treatment options continues to expand in this setting, the primary issue is determining how to tailor treatments to individual patients, Waks emphasizes.

There is a critical need to identify which patients require the most intensive treatment to achieve optimal outcomes and which patients could benefit from less aggressive therapy, thereby avoiding unnecessary treatment-related toxicity, Waks explains. The findings from the DAPHNe trial, particularly the data on ctDNA dynamics, may help address this need. By understanding the prevalence and changes in ctDNA levels, clinicians may be able to better stratify patients based on their risk and response to therapy, ultimately leading to more personalized and effective treatment strategies. The ability to monitor ctDNA could also provide valuable insights into tumor biology and response to treatment, enabling oncologists to adjust therapies in real-time. This approach could ensure that patients who are likely to benefit from more intensive treatment receive it.

Adrienne G. Waks, MD, discusses efforts to address unmet needs in HER2-positive breast cancer.

Dr Waks on Unmet Needs in Patients With HER2+ Breast Cancer

Adrienne G. Waks, MD, physician, associate director of Clinical Research, Dana-Farber Cancer Institute, instructor in medicine, Harvard Medical School, discusses treatment alternatives in the third line and beyond for patients with metastatic HER2-positive breast cancer. 

A potential treatment option for patients in the third line is the novel monoclonal anti-HER2 antibody margetuximab-cmkb (Margenza), Waks begins. Due to its immune-activating properties, margetuximab could serve as a potential substitute for trastuzumab (Herceptin) in chemoimmunotherapy regimens, Waks says. The agent was approved by the FDA in 2020 alongside chemotherapy for adult patients with metastatic HER2-positive breast cancer who received 2 or more prior HER2-targeted therapies, including 1 in the metastatic setting. The approval was supported by data from the phase 3 SOPHIA trial (NCT02492711).

Another alternative treatment option is the regimen from the phase 2 monarchHER trial (NCT02675231) of fulvestrant (Faslodex), abemaciclib (Verzenio), and trastuzumab, Waks continues. MonarcHER evaluated this triplet in patients with hormone receptor (HR)–positive, HER2-positive breast cancer previously treated with 2 or more prior lines of therapy. Although this was not a phase 3 trial, all agents are approved by the FDA, Waks notes, adding that the approach was well tolerated and does not include a chemotherapy agent. This makes it an attractive option for some patients who have been treated with chemotherapy alone or in addition to targeted therapy for several years, she explains.

Although it remains the oldest available antibody-drug conjugate (ADC) utilized in this space, strategies involving ado-trastuzumab emtansine (Kadcyla; T-DM1) remain a viable option for patients with HER2-positive disease, Waks notes. The phase 3 HER2CLIMB-02 trial (NCT03975647) is currently investigating whether adding tucatinib to T-DM1 will improve efficacy outcomes vs single-agent T-DM1 in patients with HER2-positive disease previously treated with trastuzumab or a taxane in any disease setting, she concludes.

Disclosures: Dr. Waks reports serving as a consultant or in an advisory role for AstraZeneca; she received research funding from Genentech, MacroGenics and Merck

Adrienne G. Waks, MD, discusses treatment alternatives in the third line and beyond for patients with metastatic HER2-positive breast cancer. 

Dr Waks on Later-Line Treatment Options in HER2+ Breast Cancer

Adrienne G. Waks, MD, physician, associate director of Clinical Research, Dana-Farber Cancer Institute, instructor in medicine, Harvard Medical School, discusses breast cancer survival in patients with small node-negative HER2-positive breast cancer according to the treatment modality received.

An analysis of treatment patterns and patient outcomes was conducted to clarify the benefit of systemic therapy for the treatment of patients with small, node-negative HER2-positive breast cancer across stage I tumor size.

Patients with a single lifetime diagnosis of pT1N0 HER2+ breast cancer between 2010 and 2019 were identified utilizing the national Surveillance, Epidemiology and End Results (SEER) database. Their prior exposure to chemotherapy was categorized as yes, no, or unknown. All systemic therapy was administered in the adjuvant setting. The primary objective was breast cancer-specific survival. Notably, SEER did not contain data on prior endocrine therapy or recurrence events. Within each tumor stage, patients were categorized as hormone receptor (HR)–positive (n = 9513) or HR-negative (n = 3348).

Results showed that patients with stage IA and IB tumors of 1cm or less had high rates of 5-year breast cancer-specific survival with or without chemotherapy, Waks reports. Patients with pT1a HR-positive HER2-negative disease had rates of 99.8% with chemotherapy. In the pT1B HR-positive group, this rate was 99.3%. In the HR-negative group, patients with pT1A tumors had a survival rate of 98.4% with chemotherapy, and those with pT1B tumors had a rate of 98.9%.

Moreover, patients with HR-positive pT1C tumors between 1 cm and 2 cm had survival rates of 98.7% with chemotherapy, Waks continues. Patients in this group with HR-negative tumors had a rate of 96.7%.

Larger tumors did have an increase in events, indicating that chemotherapy administration for these patients was correlated with tumor size, Waks notes. Overall, chemotherapy administration was associated with a higher breast cancer-specific survival rate in the stage IA cohort, and more specifically in patients with HR-positive, HER2-negative stage 1A tumors.

Adrienne G. Waks, MD, discusses breast cancer survival in patients with small node-negative HER2-positive breast cancer according to the treatment modality received.


Dr Waks on Survival Outcomes With Chemotherapy in Small Node-Negative HER2+ Breast Cancer

Adrienne G. Waks, MD, physician, associate director of Clinical Research, Dana-Farber Cancer Institute, instructor in Medicine, Harvard Medical School, discusses the continued evaluation of immunotherapy in HER2-positive breast cancer.

Recently published data from the phase 3 IMpassion050 trial (NCT03726879) showed that atezolizumab (Tecentriq) did not add any benefit to pathological complete response rates when added to the standard-of-care regimen of 4 cycles of dose-dense doxorubicin and cyclophosphamide, followed by paclitaxel plus pertuzumab (Perjeta) and trastuzumab (Herceptin) in combination, Waks explains. Moreover, these data were similar all for patients, including those in the intent-to-treat and PD-L1–positive populations, Waks says.

The phase 2 KATE2 trial (NCT02924883) is evaluating ado-trastuzumab emtansine (T-DM1; Kadcyla) in combination with atezolizumab in the metastatic setting, based on previous suggestive data that implied there may benefit to adding a checkpoint blockade for the PD-L1–positive subset of patients, Waks continues. Though data from KATE2 have not been read out, it is uncertain what role immune checkpoint blockade could have in HER2-positive breast cancer in the early and the later stage settings, Waks concludes.

Adrienne G. Waks, MD, discusses the continued evaluation of immunotherapy in HER2-positive breast cancer.


Adrienne G. Waks, MD

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