Laura Panjwani, OncLive

In the traditional treatment of HER2-positive breast cancer, surgery is performed first, followed by the use of chemotherapy and/or targeted agents.

However, this approach is increasingly becoming outdated, says Sunil Verma, MD, department head, Clinical Department of Oncology, Calgary Zone, medical director, Tom Baker Cancer Centre.

“Oncologists need to know that neoadjuvant treatment, as a model of care, is now becoming standard,” says Verma. “In the past, neoadjuvant treatment was restricted for locally advanced patients, but we are now using it for the majority of patients with HER2-positive disease, even those with operable tumors and sometimes in patients with tumors as small as T2.”

Several agents have been investigated for neoadjuvant use in HER2-positive disease.

In the randomized, multicenter phase II NeoSphere trial, the combination of pertuzumab (Perjeta), trastuzumab (Herceptin), and chemotherapy as a neoadjuvant therapy for adult patients with HER2-positive breast cancer proved to be beneficial.

In a 5-year analysis presented at the 2015 ASCO Annual meeting, the pathological complete response rate (pCR) rate was 39.3% for the pertuzumab regimen compared with 21.5% with trastuzumab and chemotherapy alone (

 = .0063). Additionally, the risk of disease progression or recurrence was reduced by 31% and 40%, respectively, with the addition of pertuzumab to trastuzumab and chemotherapy compared with trastuzumab and chemotherapy alone.

The ADAPT study, a large umbrella trial that has enrolled 5000 patients with various breast cancer phenotypes, demonstrated a benefit for neoadjuvant ado-trastuzumab emtansine (T-DM1; Kadcyla) in HER2-positive breast cancer.

The trial included 376 patients with HER2-positive and HR-positive breast cancer who were randomized to receive neoadjuvant T-DM1 at 3.6 mg/kg with or without endocrine therapy or trastuzumab plus endocrine therapy. Treatment was administered for 4 cycles followed by surgery and 1 year of standard adjuvant chemotherapy plus trastuzumab.

The pCR rate was found to be substantially higher in the T-DM1 arms compared with trastuzumab plus endocrine therapy (

 <.001). In the T-DM1—alone arm (n = 37), the pCR rate was 40.5%. In the arm with T-DM1 plus endocrine therapy (n = 48), the pCR rate was 45.8%. In the arm with trastuzumab plus endocrine therapy (n = 45), the pCR rate was 6.7%.

, Verma discusses emerging key agents in the neoadjuvant setting, advantages of treating prior to surgery, and questions that still remain regarding HER2-positive neoadjuvant therapy.

OncLive: What are the biggest advantages to neoadjuvant therapy?

: The rationale behind neoadjuvant therapy is that we have quicker access to systemic therapy, and we have an opportunity to establish whether patients achieve pCR or not. We also have the opportunity to integrate better therapies, including trastuzumab and now pertuzumab in the United States. We can also use it identify which patients will not do as well by examining those patients who did not achieve a pCR. Those patients can then be considered for future trials.

If you are going to give treatment to a patient with HER2-positive breast cancer and their tumors are palpable, they should receive neoadjuvant therapy.

Can a pCR in the neoadjuvant setting be used as a surrogate for disease-free survival (DFS) or overall survival (OS)?

The relationship between pCR and OS has been more established for ER-negative/HER2-positive patients than for ER+/HER2+ patients. The ER+/HER2+ patients do not have the same type of relationship, probably because many of them will end up receiving antiestrogen therapy behind their current neoadjuvant therapy, and it is hard to establish a relationship by just looking at pCR. However, for ER+/HER2+ patients, I think that model and the relationship between pCR and OS is quite strong.

What agents are being investigated for the treatment of HER2-positive breast cancer in the neoadjuvant setting?

The agents that have been identified as standard of care include chemotherapy, trastuzumab, and pertuzumab. Pertuzumab has been shown to be associated with improved pCR and the preliminary results from the NeoSphere trial also show that there is a favorable DFS benefit.

However, we are awaiting the results of the AFFINITY trial to really confirm the magnitude of benefit in the adjuvant setting. The other agent that has been investigated in this setting is T-DM1. Data from the ADAPT trial, which was conducted in Germany, showed that HR-positive and HER2-positive patients, when given T-DM1 for just 4 cycles, had a pCR rate of about 40%. This is quite a significant level of activity seen for this subset of patients.

Another agent that has been studied quite extensively in this area is neratinib, which is an oral small tyrosine kinase inhibitor. This has been shown to be associated with superior pCR when compared with trastuzumab when given in combination with paclitaxel. This was demonstrated in the FB-7 study.

There are a number of other clinical trials, which have completed accrual and we will get the results of this year. These include the KRISTINE study, which is investigating TCH (docetaxel, carboplatin, and trastuzumab) with pertuzumab versus T-DM1 plus pertuzumab. The 2 arms will be compared head-to-head, and we will get the data from this study later this year.

How far are we from neoadjuvant therapy being utilized to delay or to replace the need for surgery?

We are not there at the present time; however, there is a lot of interest to see if we can measure treatment response earlier or use different modalities to measure treatment response other than surgery. Other options include utilizing ultrasound or perhaps doing biopsies in the tumor bed to determine if any viable tumor cells remain, and then randomizing patients to receive immediate surgery or follow-up. However, there are no studies at present time.

Do you see HER2-positive neoadjuvant treatment continuing to evolve in the coming years?

This is an important space. We need to consider neoadjuvant treatment as the standard of care because many trial designs will now incorporate this model. Whether it is investigating new drugs, new approaches, or new therapies for patients who don’t achieve pCR, it can be evaluated in this setting. It is so important to continue to investigate approaches other than the standard approach of surgery followed by chemotherapy.

Gianni L, Pienkowski T, Im Y-H, et al. Five-year analysis of the phase II NeoSphere trial evaluating four cycles of neoadjuvant docetaxel (D) and/or trastuzumab (T) and/or pertuzumab (P). J Clin Oncol. 2015;33 (suppl; abstr 505).

Harbeck N, Gluz O, Christgen M, et al. Efficacy of 12-weeks of neoadjuvant T-DM1 with or without endocrine therapy in HER2-positive hormone-receptor-positive early breast cancer: WSG-ADAPT HER2+/HR+ phase II trial. J Clin Oncol. 2015;33 (suppl; abstr 506).

Articles

Several chemotherapy agents have been investigated for neoadjuvant use in HER2-positive breast cancer.