When Is De-escalating Systemic Therapy Appropriate in Low-Risk Breast Cancer?

Years ago, most patients with breast cancer received high-dose chemotherapy, radiation and surgery. Fortunately, as therapies have improved, clinicians are discovering opportunities to appropriately de-intensify treatment. Cleveland Clinic Cancer Institute recently published a report in JCO Oncology Practice highlighting the latest thoughts on treatment de-escalation.

The report’s authors noted the importance of multidisciplinary decisions when it comes to de-escalation. Breast cancer therapy decisions include what radiation is appropriate, what is the best surgical management of the axilla and ultimately what systemic therapy is needed. It’s essential that these disciplines work together to find out where we can de-escalate,” says oncologist Azka Ali, MD.

Background

Each therapy offers different gains and they work in concert with one another. For example, radiation helps protect against local recurrence while systemic therapy offers protection from distant recurrence.

Yet all breast cancer treatments come with risks. Patients may have post-operative pain, neuropathy or lymphedema after surgery, skin changes after radiation or a host of side effects from chemotherapy. “The treatment should not be worse than the cancer itself,” says Dr. Ali. “All those treatments have the potential to adversely affect our patients and leave them with potentially long-term toxicities, which is why we look for ways to safely eliminate treatment elements where possible.”

Opportunities to de-intensify systemic therapy

Clinicians are now able to de-intensify therapy under several different scenarios, including:

• Omitting chemotherapy for patients with hormone receptor positive, HER2 negative breast cancer

Genomic tests can estimate the risk of cancer coming back and whether the patient is likely to benefit from chemotherapy. If a tumor is not likely to benefit from chemotherapy, then chemotherapy can be safely omitted. Several of these FDA-approved genomic tests are covered by insurance.

Genomic testing is often performed at the time of surgery but if the tumor appears quite aggressive or there is lymph node involvement, the clinician may perform the test prior to surgery (on the biopsy tissue) to determine if chemotherapy has the potential to shrink the tumor before surgery.

• Omitting chemotherapy for patients with HER2 positive breast cancer

Clinicians used to prescribe a heavy chemotherapy regimen for HER2 positive breast cancer. With the introduction of a second HER2 blocker (pertuzumab), they’ve learned that using the dual HER2 blockage of pertuzumab (in addition to trastuzumab) obviates the need for a heavy chemotherapy backbone. In the HER2 positive space, this resulted in backing off from the use of Adriamycin-based chemo or anthracycline-based chemo, which had the potential to cause cardiac toxicity, and has a low risk of secondary bone marrow cancer.

• Using imaging guidance to determine if chemotherapy can be omitted for patients with HER2-positive early breast cancer

The PHERgain trial also demonstrated another approach to de-escalation for HER2-positive early breast cancer. In this case, patients were randomized to one of two groups. One group received the traditional chemotherapy, trastuzumab, and the other group received trastuzumab and pertuzumab. Patients were then stratified based on PET-guided response, meaning PET responders were allowed to remain on trastuzumab/pertuzumab and complete the six planned cycles. PET non-responders received the regimen of chemotherapy, trastuzumab and pertuzumab.

The three-year follow-up demonstrated that the group that only received trastruzumab/pertuzumab did reach an invasive disease-free survival threshold that was pre-specified. This study showed that there may be a select group of patients who can safely omit chemotherapy. “This is a fantastic way to de-escalate, because the goal is to safely omit therapy where possible,” says Dr. Ali.

• Reducing chemotherapy regimens for metastatic stage 4 breast cancer patients

The current thinking is that single-agent chemotherapy is effective for patients with stage 4 metastatic disease. “We don’t routinely administer multi-agent regimens to these patients, as we often achieve an adequate response and spare unnecessary toxicities,” says Dr. Ali.

• Shortening endocrine therapy where appropriate

Endocrine therapy can cause menopause-like side effects such as hot flashes, night sweats, bone pain, mood changes and hair thinning. Longer lasting symptoms include joint issues or bone density loss. In younger patients, there is the added concern about its effect on cardiac health and their lipid profile.

To address these concerns, clinicians can utilize some additional tests to estimate the benefit of a longer duration of anti-estrogen therapy. One FDA-approved test is the Breast Cancer Index test, which can be offered to select early-stage patients to estimate if they would benefit from a prolonged course of anti-estrogen therapy. For very high-risk patients, clinicians may discuss a prolonged course of anti-estrogen therapy based on the individual cancer risk.

The test offers predictive ability as to whether a patient will benefit from a prolonged duration of endocrine therapy or not. “If not, we can spare them the additional toxicity that may accrue from more years on endocrine therapy,” says Dr. Ali. Based on the test results, clinicians may reduce the number of years the patient remains on the therapy.

What’s next

The active question in the oncology community is whether select high-risk HER2 positive breast cancer patients can forgo upfront chemotherapy.

Typically, for early stage (stage 1) cancers, if the tumor is less than 2 mm and there is no lymph node involvement, patients can get their breast cancer surgery first and then receive postoperative systemic therapy based on the final pathology (usually consisting of a chemotherapy/HER2 blocker combination). Those who are clinically high risk receive a four-regimen treatment (two courses of chemotherapy and two courses of HER2 blockers).

The COMPASS HER2 trial is studying whether patients can safely forgo carboplatin and achieve equivalent outcomes. Those results remain eagerly awaited.