Novel Sequencing Strategies May Expand Localized and Metastatic Breast Cancer Treatment Landscapes


Jairam Krishnamurthy, MD, FACP, highlights the benefits of neoadjuvant therapy in early-stage HER2-positive breast cancer, treatment considerations for patients with HER2-negative disease who have progressed on an initial CDK4/6 inhibitor, and ongoing research that may address unmet needs in the field.

Jairam Krishnamurthy, MD, FACP

Jairam Krishnamurthy, MD, FACP

An influx of research on the horizon may contribute to improved treatment outcomes for patients with early-stage and metastatic HER2-positive breast cancer, according to Jairam Krishnamurthy, MD, FACP. He added that additional data, such as long-term follow-up data from the phase 3 NATALEE trial (NCT03701334) are necessary to confirm the role of CDK4/6 inhibitors in patients with HER2-negative disease.

In NATALEE, patients with hormone receptor (HR)–positive/HER2-negative metastatic breast cancer achieved a 3-year invasive disease–free survival rate of 90.4% with adjuvant ribociclib (Kisqali) plus endocrine therapy vs 87.1% with endocrine therapy alone (hazard ratio, 0.748; 95% CI, 0.618-0.906; P = .0014). However, Krishnamurthy emphasized that these data are immature, as only 20.2% of patients had completed 3 years of ribociclib treatment as of the data cutoff date of January 11, 2023.1

In patients with metastatic HER2-positive disease, including those with brain metastases, the phase 2 HER2CLIMB trial (NCT02614794) demonstrated that the combination of tucatinib (Tukysa), trastuzumab (Herceptin), and capecitabine (Xeloda) elicited a median overall survival of 24.7 months vs 19.2 months with placebo plus trastuzumab and capecitabine (hazard ratio, 0.73; 95% CI, 0.59-0.90; P = .004), findings which Krishnamurthy says have led to the initiation of further research with tucatinib in this population.2

“[There are] exciting times ahead for breast cancer [research], as well as for breast cancer providers and patients, because these trials mean that there could be many more options for patients, which could then translate into better outcomes,” Krishnamurthy said in an interview with OncLive® following a State of the Science Summit™ on breast cancer, which he chaired.

In the interview, Krishnamurthy highlighted key points presented at the meeting, including the benefits of neoadjuvant therapy in early-stage HER2-positive breast cancer, treatment considerations for patients with HER2-negative disease who have progressed on an initial CDK4/6 inhibitor, and ongoing research that may address unmet needs in the field.

Krishnamurthy is an associate professor of medicine in the Division of Hematology and Oncology and codirector of the Breast Cancer Program at the University of Nebraska Medical Center in Omaha.

OncLive: Regarding your presentation on managing early-stage HER2-positive breast cancer, what are some of the advantages of using neoadjuvant systemic therapy in this population?

Krishnamurthy: The advantages of neoadjuvant systemic therapy in HER2-positive breast cancer are multifold. One, we can see in real time how much shrinkage of the tumor we can achieve and how responsive the tumor is to systemic therapy. Secondly, it helps us determine what should be done at the back end of the surgery, in the adjuvant setting, based on whether the patient achieves pathologic complete response. At the same time, it does not compromise the primary purpose of systemic therapy, which is to reduce the risk of distant recurrence.

Regardless of whether patients receive neoadjuvant or adjuvant therapy, they still derive benefit [from that therapy]. [However] neoadjuvant [therapy] has the added benefits of real-time shrinkage that we can see. [It also gives us the ability to make treatment decisions] regarding prognostic and predictive factors, such as how to treat adjuvantly and what the risk of recurrence would be based on whether there is cancer on the final surgical specimen.

What are the current neoadjuvant systemic therapy options for these patients?

Typically, there are various options. One is using a taxane with trastuzumab and pertuzumab [Perjeta]. You could also consider a taxane with carboplatin, trastuzumab, and pertuzumab, but that option is sometimes less well tolerated than the first one. That’s where there are various trials ongoing trying to assess whether carboplatin is needed in this setting. If patients have [tumors measuring] less than 2 centimeters and lymph node–negative cancer, we could also consider a taxane with trastuzumab as neoadjuvant therapy, but that’s less often used.

Turning to your other presentation on managing metastatic HER2-positive breast cancer, how has the HER2CLIMB trial paved the way for additional trials that include patients with brain metastases?

The HER2CLIMB trial was a landmark study in terms of how it showed that a compound could cross the blood-brain barrier and show excellent activity in the intracranial space, which is where we were struggling with patients with HER2-positive breast cancer, because this type of disease can have a propensity to go to the brain. How it has paved the way for subsequent trials is that now there is renewed interest in combination therapies with tucatinib to see if those have greater efficacy both inside the brain as well as outside. That’s where the [phase 3] HER2CLIMB-02 [NCT03975647] and [phase 2] HER2CLIMB-04 [NCT04539938] trials are being conducted, where tucatinib is either being combined with ado-trastuzumab emtansine [T-DM1; Kadcyla] or fam-trastuzumab deruxtecan-nxki [(Enhertu), respectively].

Your colleague Meghana Kesireddy, MBBS, of the University of Nebraska Medical Center, gave a presentation on CDK4/6 inhibition in HER2-negative breast cancer. What research may support the use of an additional CDK4/6 inhibitor after progression on an initial CDK4/6 inhibitor plus endocrine therapy in this population?

A few trials have [assessed] the role of a CDK4/6 inhibitor beyond progression on a CDK4/6 inhibitor. Initially, we heard about the [phase 2] PACE trial [NCT03147287], which [evaluated] continuing palbociclib [Ibrance] after progression on palbociclib and was unfortunately a negative trial. We also heard about the [phase 2] MAINTAIN trial [NCT02632045], which [investigated giving] palbociclib initially in 86.5% of patients [who], upon progression, switched to ribociclib. A few other [patients previously] received ribociclib [or abemaciclib (Verzenio)]. That approach seems to have a better progression-free survival than the standard of care [SOC], where you would not do such an approach. This was an investigator-initiated phase 2 study. We need confirmation with a larger study, but at least it forms the basis for thinking along those lines that one could potentially consider switching to ribociclib upon progression. [These are] early days, and we need confirmatory, larger phase 3 randomized studies before that becomes SOC.

Praveen Vikas, MBBS, of the University of Iowa in Fairfield, discussed endocrine-based therapy in HER2-negative breast cancer. How have the findings from the NATALEE trial informed the potential benefits of ribociclib in this population?

NATALEE was an important study presented at the 2023 ASCO Annual Meeting. A broader group of patients were enrolled in the trial compared with the [phase 3] monarchE trial [NCT03155997] with abemaciclib. In this study, patients with lymph node–negative disease were also included, [as well as those] with smaller tumors, although they needed to have slightly higher-risk features in terms of genomic risk and higher-grade tumors.

With this being a positive study at this time, although the results are premature because only 20.2% of the patients have completed 3 years of ribociclib, there is definite interest and excitement regarding how the final results could pan out after all patients have completed 3 years of adjuvant ribociclib. At that time, we may be able to offer this agent to a wide variety of patients with HR-positive, HER2-negative, localized breast cancer, which could result in better outcomes for those patients. In short, [there are] exciting times ahead, but we need longer-term data before we can confirm that.

What ongoing breast cancer research at the University of Nebraska Medical Center is important to note?

We have a [phase 2] neoadjuvant investigator-initiated trial [NCT05069038][using] neoadjuvant palbociclib and letrozole for patients with localized HR-positive and HER2-negative breast cancer, [in which we are] reassessing their Ki67 index on a biopsy done 4 weeks after the initiation of therapy. If that number is less than 10%, they can continue the same 2 drugs, palbociclib and letrozole, for 5 more months before undergoing surgery. We’re also doing genomic analyses on the initial biopsy, again at 4 weeks, and at the end of treatment to see how the genomic signature changes with neoadjuvant therapy, which has not been reported much.

This is an important study trying to see [which] patients with HR-positive and HER2-negative breast cancer could potentially benefit from a non-chemotherapy approach. Potentially, we could avoid chemotherapy in [that population]. How does endocrine therapy [plus] targeted agents help with downstaging disease and potentially converting patients requiring mastectomy to patients being able to undergo lumpectomy, which is a much lower-risk surgery?

The other study I would like to highlight is the [phase 2] CompassHER2-pCR trial [NCT04266249] that we have at our institution. [That trial is evaluating] a neoadjuvant taxane plus trastuzumab and pertuzumab in patients with HER2-positive breast cancer, where they receive these 3 drugs for 4 doses. Adjuvantly, we also have the [phase 3] CompassHER2 RD study [NCT04457596], which is randomizing patients with residual [HER2-positive] disease to T-DM1 vs T-DM1 plus tucatinib.

What is your main message for colleagues regarding the breast cancer treatment landscape?

Several agents are moving ahead in earlier lines of therapy in the metastatic setting as well as in localized disease, both in the HER2-positive, HR-positive and triple-negative breast cancer arenas. Similarly, in the HER2-low setting, there’s a lot of movement happening with newer compounds and with existing compounds moving into the adjuvant and neoadjuvant settings.

Disclosures: Dr Krishnamurthy reports advisory board roles with AstraZeneca and Gilead.


  1. Slamon DJ, Stroyakovskiy D, Yardley DA, et al. Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2- early breast cancer: primary results from the phase III NATALEE trial. J Clin Oncol. 2023;41(suppl 17):LBA500. doi:10.1200/JCO.2023.41.17_suppl.LBA500
  2. Curigliano G, Mueller V, Borges V, et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis. Ann Oncol. 2022;33(3):321-329. doi:10.1016/j.annonc.2021.12.005
Related Videos
Peter Schmid, MD, PhD
Seema A. Khan, MD
Javier Cortés, MD, PhD,
Stephanie L. Graff, MD
Senthil Damodaran, MD, PhD
Jason Jincong Freeman, PhD
Heather A. Parsons, MD, MPH
In this final episode of OncChats: Reviewing Best Practices in the Surgical Management of Breast Cancer, Gladys Giron, MD, FACS, and Cristina Lopez-Peñalver, MD, shed light on clinical outcomes following surgery of the primary tumor in patients with stage IV breast cancer.
Paolo Tarantino, MD
Erica L. Mayer, MD, MPH