Does Size Matter? Determining the Size Threshold for Treating Invasive HER2-Positive Breast Cancer

“In the 1990s, there was a brief period of time that we had testing for HER2—the most worrisome, dreaded, and aggressive breast cancers—and no trastuzumab,” said Patrick I. Borgen, MD, Chair, Department of Surgery, Maimonides Medical Center, Brooklyn, NY, and Program Chair for the 37th Annual Miami Breast Cancer Conference. “We sometimes forget about that time, because of the incredibly effective agents we have and the incredible explosion of new agents. But untreated, HER2 is certainly a scary entity.”

Now that effective agents exist for treating HER2-positive disease, more targeted questions can be answered, namely, “What is the size threshold for treating HER2-positive tumors?” More specifically, “Should all patients with HER2-positive tumors between 1 cm and 2 cm receive neoadjuvant chemotherapy?”

In a medical crossfire debate, moderator Dr Borgen asked Sara Hurvitz, MD, Director, Breast Cancer Clinical Trials Program, UCLA Health, Los Angeles, and Don Dizon, MD, Director, Women’s Cancers, Lifespan Cancer Institute, Providence, RI, to debate the role of neoadjuvant chemotherapy in tumors between 1 cm and 2 cm, as well as the size threshold for treating invasive HER2-positive breast cancer.

The Argument in Favor of Neoadjuvant Chemotherapy

“I’m postulating that biology, not tumor size, should be driving the decision about neoadjuvant therapy,” said Dr Hurvitz. Since about 2013, the use of neoadjuvant treatment has steadily increased with the availability of better agents, even in smaller tumors.

“So why would we choose neoadjuvant therapy?” she asked. “If a patient needs systemic therapy anyway, particularly if that patient is young, why not do it before surgery?”

Neoadjuvant chemotherapy increases breast-conserving surgery rates, and studies have shown similar rates of disease-free and overall survival in the neoadjuvant and adjuvant settings.

“Using neoadjuvant therapy in the setting of the clinic allows us to monitor response and adjust systemic therapy if we need to,” Dr Hurvitz said. “And now we know that residual cancer after neoadjuvant systemic therapy is highly prognostic.”

In analyzing responses based on tumor subtypes, patients with HER2-positive, hormone receptor–negative disease have shown the highest likelihood of achieving pathologic complete response with neoadjuvant systemic therapy. Moreover, the prognostic impact of having a pathologic complete response after treatment is a lower likelihood of relapse in subsequent years. 

Residual disease after neoadjuvant therapy identifies those at particular risk for relapse, and according to Dr Hurvitz, “now we have a therapy that allows us to intervene.”

In the practice-changing phase 3 KATHERINE clinical trial, adjuvant treatment with trastuzumab emtansine (T-DM1) reduced the risk for invasive disease by 50% and improved distant recurrence rates in patients with HER2-positive early breast cancer and residual disease after neoadjuvant chemotherapy. All subgroups benefited, even those with a very small amount of residual disease at the time of surgery.

“So, we can now impact patients who have a high risk for recurrence, by virtue of the fact that they have residual disease,” she said.

Finally, Dr Hurvitz argued that the imaging of dense breast tissue limits the ability to accurately predict size, so if a patient is taken directly to surgery and the tumor is >2 cm, the opportunity to give neoadjuvant chemotherapy has been lost.

“We also have an opportunity to de-escalate systemic therapy in the neoadjuvant setting and then escalate in the adjuvant setting with T-DM1 if there is residual disease at the time of surgery,” she said.

The Alternative View

Dr Dizon asked audience members to remember why patients are treated with neoadjuvant therapy.

“We do neoadjuvant therapy for the goal of less surgery,” he said. “For women who are initially inoperable, we do neoadjuvant therapy to render them operable. For women looking at a mastectomy, we render the therapy so they can be candidates for breast conservation. That is the only primary indication for giving neoadjuvant chemotherapy.”

Although he acknowledged that its additional use does provide prognostic information, the totality of the data does not show that neoadjuvant therapy improves survival compared with adjuvant treatment.

For patients with HER2-positive small tumors, adjuvant treatment is associated with excellent outcomes. “The word here is ‘de-escalation,’” Dr Dizon said. “And the outcomes are outstanding.”

In the ATEMPT clinical trial, a de-escalated adjuvant approach with T-DM1 led to 98% disease-free survival at 3 years among women with HER2-positive breast cancer and small tumors.

“People with small HER2-positive breast cancers (1 cm to <2 cm) do exceptionally well and don’t need a ton of treatment,” he said. “For the 50% of patients who don’t achieve a pathologic complete response, they’re going to require further treatment, and in my opinion that is not de-escalation.”

Since these patients do not require mastectomy, he argued that there is no surgical reason to give them neoadjuvant chemotherapy.

The neoadjuvant treatment that would probably be offered to these patients based on the extrapolated data, he added, is not paclitaxel and trastuzumab. “It would likely be TCHP [docetaxel + carboplatin + trastuzumab + paclitaxel],” Dr Dizon said. “So, you’re also subjecting them to significant toxicity.”

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