Gabriel N. Hortobagyi, MD, Delivers the William I. McGuire Memorial Lecture

Caroline Helwick

March 2013, Highlights - Chemotherapy

The honor of delivering the William I. McGuire Memorial Lecture at this year’s meeting went to Gabriel N. Hortobagyi, MD, FACP, Professor of Breast Medical Oncology and Nellie B. Connally Chair in Breast Cancer at the University of Texas M.D. Anderson Cancer Center, Houston. Dr McGuire cofounded the San Antonio Breast Cancer Symposium in 1977.

Neoadjuvant Systemic Therapy: Promising Experimental Model or Improved Standard of Care?

Neoadjuvant systemic therapy is a treatment strategy that has been used for more than 30 years but its role is still evolving. The concept emerged after anthracycline-containing combination regimens showed dramatic responses in large primary tumors: almost 90% of patients achieved at least a 50% reduction in measurable tumors, and approximately 10% achieved complete remissions (CRs).

When used earlier in the preoperative setting, anthracycline-based regimens became a means of improving the management of largely inoperable breast cancer. Eventually, in efforts led largely by Dr Hortobagyi, it was learned that clinical response to neoadjuvant chemotherapy would predict for overall survival (OS).

Dr Hortobagyi’s team at M.D. Anderson Cancer Center, and others, pioneered multidisciplinary strategies consisting of neoadjuvant chemotherapy followed by surgery and radiotherapy. Such strategies rapidly became the standard of care for patients with locally advanced breast cancer and with inflammatory breast cancer, improving local control rates to more than 80% and 5-year OS rates to more than 30%, he said.

“In the early 1980s, we described the concept of pathological CR and its correlation with favorable long-term overall survival,” he continued. A Cochrane review concluded that preoperative chemotherapy compared with adjuvant chemotherapy was associated with equivalent OS and disease-free survival (DFS), and increased breast conservation rates. Although local-regional recurrence rates were increased with neoadjuvant therapy, this was not seen when surgery was part of the management.

The Importance of Achieving pCR

The achievement of a pathological CR (pCR) was associated with much better OS (hazard ratio [HR], 0.48) and DFS (HR, 0.48), the Cochrane investigators noted. But more recently, the impact of pCR on prognosis has been shown to vary according to the molecular subtypes that are now recognized. DFS is significantly better when pCR is achieved, in the case of luminal B/HER2-negative, nonluminal/HER2-positive, and triple-negative tumors; however, pCR is not associated with prognosis in luminal A tumors or in luminal B/HER2-positive tumors, he said.

Dr Hortobagyi explained that “patients with hormone receptor–positive (luminal A and luminal B/HER2-positive) tumors receive their primary systemic therapy (ie, endocrine treatment) after surgery. Therefore, pCR cannot possibly predict long-term outcomes. And patients with luminal B/HER2-negative cancer have primary resistance to endocrine therapy, so pCR reflects entirely the benefit from systemic therapy (ie, chemotherapy). In all other subtypes, pCR is highly predictive.”

Along with intrinsic subtype, a number of clinical and pathological factors predict pCR: tumor grade (high vs low), estrogen receptor (high vs low), HER2 status (high vs normal), histological type (ductal vs lobular), proliferation markers (high vs low), speed of clinical response (rapid vs slow), MDR1 gene expression (yes vs no), and extent of disease (stage III vs I).

“But there is no individual pathological or molecular marker that can predict response to primary chemotherapy in an individual patient,” Dr Hortobagyi emphasized, “although patients with estrogen receptor–negative, high-grade tumors and high S-phase fraction (or Ki67) are more likely to respond than [patients with] tumors with the opposite characteristics.”

A number of studies have attempted to correlate results in the neoadjuvant setting with outcomes, but more data are needed, he said. “We are awaiting with great interest the results of ALTTO, E5103, BETH, APHINITY, and other trials to determine whether promising results in the neoadjuvant setting uniformly translate into improved long-term outcomes,” he commented.

The Bottom Line on Neoadjuvant Systemic Therapy

Dr Hortobagyi summarized the current state of neoadjuvant systemic therapy this way:

  • Does it downstage primary tumor and axillary lymph node involvement? Clearly, yes
  • Does it increase breast conservation rates? Clearly, yes
  • Does it affect local control? Not without optimal multidisciplinary planning
  • Does it affect survival? Maybe. The survival effect needs to be assessed in patients with HER2-positive and triple-negative breast cancer.

Is neoadjuvant chemotherapy an acceptable alternative outside of a clinical trial? It is the treatment of choice for patients with locally advanced and inflammatory breast cancer, and it is an acceptable and preferred alternative to surgery followed by adjuvant chemotherapy for most patients with T2 and T3 tumors.

“Preoperative systemic therapy is optimal for all patients who are candidates for systemic therapy, and it should be tailored to the biological profile of the primary tumors. If the indication for systemic therapy is uncertain, surgical removal is preferable,” Dr Hortobagyi noted.

“Preoperative systemic therapy is not indicated,” he continued, “when systemic therapy is not indicated, primary and/or lymph node metastases cannot be measured and monitored, the patient is not compliant, and a multidisciplinary team is not available.”

Neoadjuvant chemotherapy is also “an excellent translational research tool” and, as such, will have some novel applications in the future, Dr Hortobagyi predicted. It will have a role in drug development; it will offer a means of monitoring biologic end points; and, when incorporated into randomized trials, it will justify or allow for the avoidance of randomized adjuvant trials.