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From OncoLog, April 2012, Vol. 57, No. 4

Biology, More Than Chemotherapy Timing, Drives Locoregional Recurrence in Patients Who Undergo Breast-Conserving Therapy

By Joe Munch

Photo: Mammograms
Mammograms taken before (top) and after neoadjuvant chemotherapy show a reduction in tumor size. The tumor was then removed by lumpectomy with wide surgical margins. Reprinted with permission from Kuerer’s Breast Surgical Oncology, ©McGraw-Hill 2010.

The management of breast cancer, like that of many cancers, often requires a little bit of everything: surgery, radiation therapy, and systemic therapy with chemotherapeutic drugs or other agents.

In patients with early-stage breast cancer, breast-conserving therapy (segmental mastectomy [lumpectomy] with whole-breast irradiation) is offered whenever feasible to preserve as much of the patient’s breast tissue as possible. For decades, neoadjuvant chemotherapy has been given in selected patients to shrink tumors to a size that facilitates breast-conserving therapy. Until recently, however, no large studies had compared the long-term outcomes of patients who received chemotherapy before breast-conserving therapy with those of patients who received chemotherapy after breast-conserving therapy.

A new study from The University of Texas MD Anderson Cancer Center has found that the timing of chemotherapy does not affect the risk of locoregional recurrence in patients with breast cancer undergoing breast-conserving therapy and that this risk in fact is driven by the underlying biology of the tumor. The findings underscore the importance of taking a multidisciplinary approach to treating breast cancer.

Timing chemotherapy


The study, which included nearly 3,000 women who underwent breast-conserving therapy at MD Anderson between 1987 and 2005, compared the locoregional recurrence rates of patients who underwent surgery first to those of patients who underwent chemotherapy first. Patients with inflammatory breast cancer, for whom neoadjuvant chemotherapy is the standard of care, were not included in the study.

“We found that if you grouped patients by their stage of disease at presentation, it didn’t matter whether you did surgery first or gave chemotherapy first; we had similar rates of locoregional control, suggesting that breast-conserving therapy after neoadjuvant chemotherapy is a viable option in carefully selected patients,” said Elizabeth Mittendorf, M.D., an assistant professor in the Department of Surgical Oncology at MD Anderson and the first author of the study’s report.

The study’s findings confirmed what has long been suspected among those familiar with giving chemotherapy before breast-conserving therapy in appropriately selected patients.

“I’m not sure that the results of the study will change our practice, but rather, they give us some confirmation that we should continue to feel this approach is safe and effective,” said co-author Thomas Buchholz, MD, a professor in and head of the Division of Radiation Oncology. “With careful multidisciplinary coordination and appropriate selection criteria, using chemotherapy followed by lumpectomy and radiation offers patients excellent outcomes and may enable patients with larger primary tumors to avoid mastectomy.”

The MD Anderson approach

“At MD Anderson, our approach for a long time has been that if someone will need chemotherapy, we consider giving it first, before surgery. For example, patients with tumors larger than 5 cm and patients with disease in their lymph nodes are likely to benefit from chemotherapy first,” Dr. Mittendorf said.

“MD Anderson physicians are very comfortable with giving chemotherapy in the neoadjuvant setting, but some surgeons don’t have the same level of comfort with the practice as we do,” Dr. Mittendorf said. “Their concern is that giving chemotherapy first may interfere with appropriate surgical management.”

For example, there is some hesitancy about performing breast-conserving surgery after chemotherapy because of concerns that chemotherapy will complicate assessment of the completeness of surgery. Generally, tumors that respond to chemotherapy either shrink concentrically, becoming smaller but remaining intact, or “crumble” into several smaller tumors. When a tumor crumbles, nests of the tumor can be left behind after surgery and continue to grow and metastasize, a possibility that raises the question of how much breast volume must be removed to ensure the complete resection of the tumor.

To address this concern at MD Anderson, patients’ tumors are evaluated with mammography and ultrasonography both before and after neoadjuvant chemotherapy is given. These images help guide surgery. The goal of surgery is to attain at least a 2-mm margin of normal tissue. Patients with localized disease that responds well to neoadjuvant chemotherapy—those in whom a lumpectomy can be performed with negative margins—are excellent candidates for breast-conserving therapy, whereas patients in whom lumpectomy cannot be performed with negative margins are candidates for mastectomy.

“One important aspect of our approach is that we do not routinely excise the prechemotherapy volume.” Dr. Mittendorf said. “Instead, we resect any residual tumor or calcifications identified on imaging studies done after neo-adjuvant chemotherapy has been completed.”

Weighing the benefits

If adjuvant and neoadjuvant chemotherapy result in similar locoregional recurrence rates, what guides the selection between them?

Offering surgery first has its benefits—it facilitates detailed pathological evaluation of the tumor, and in patients anxious about having a tumor remain inside their bodies while they receive 6 months of chemotherapy, immediate surgery provides some peace of mind.

However, giving chemotherapy first offers its own set of benefits. According to Ana Gonzalez-Angulo, M.D., an associate professor in the Department of Breast Medical Oncology, the main benefit is that neoadjuvant chemotherapy increases the percentage of patients who are eligible for breast-conserving therapy.

Because chemotherapy often shrinks the tumor, women with locally advanced, unresectable breast tumors can become candidates for mastectomy, and women with tumors so large that they would require mastectomy can become candidates for breast-conserving therapy.

Another advantage is that neoadjuvant chemotherapy allows oncologists to see in vivo whether the treatment is working. When chemotherapy is given after surgery, there is no way of assessing the tumor’s response; one can only really know that the therapy did not work if the cancer has recurred.

“Using chemotherapy up front allows you to make sure you are giving the right chemotherapy drugs. Obviously, if you removed the tumor first, you would be unable to tell that,” Dr. Buchholz said. “It also may decrease the chance that patients will need extensive axillary lymph node removal.”

“Neoadjuvant chemotherapy is kind of like a biological test of the tumor. I can see whether the tumor is responding to different chemotherapeutic agents,” Dr. Mittendorf said. “I recently had a patient whose tumor actually grew when we started paclitaxel, so we immediately converted her regimen to FAC [fluorouracil, doxorubicin, and cyclophosphamide], and the tumor shrank. If we had done her surgery first, we would have given her the standard 12 full courses of paclitaxel, which we wouldn’t have known was not effective in her, followed by the FAC.”

Giving chemotherapy first also enables oncologists to prepare—and prepare patients—for potential treatment challenges ahead.

“We know that patients who have no residual disease—a complete response—by the end of neoadjuvant chemotherapy at the time of surgery tend to have a great prognosis,” Dr. Gonzalez-Angulo said. “On the other hand, patients who have a lot of residual disease after neoadjuvant chemotherapy are probably going to have a relapse within the next few years.”

Biology-driven

The MD Anderson study of neoadjuvant chemotherapy also found that several biological factors, including presenting disease stage, tumor grade, estrogen receptor (ER) status, and the presence of lymphovascular invasion or multifocal disease, predicted locoregional recurrence.

“From these data, we concluded that in certain patients, whether or not the cancer recurs is driven primarily by the biology of the tumor and less by the timing of their chemotherapy,” Dr. Mittendorf said. “In fact, it’s the biology of the tumor that’s driving the risk of recurrence, the risk of distant disease, and likely the risk of death.”

Dr. Buchholz added, “I think in every discipline—surgery, medical oncology, radiation oncology—we now are recognizing that when we say ‘breast cancer’ we are combining a host of different classes of disease that vary not just by the extent of disease but by the intrinsic biology.”

Many of these biological subcategories are characterized by the presence or absence of ER and/or human epidermal growth factor receptor 2 (HER2). Both of these proteins affect how a patient’s disease responds to systemic therapies and radiation. For example, ER-negative tumors tend to be highly responsive to chemotherapy but do not respond to hormonal therapy, whereas ER-positive tumors tend to be less responsive to chemotherapy but very responsive to hormonal therapy.

Progesterone receptor (PR) status also plays a role. Triple-negative breast cancers (those that are negative for ER, PR, and HER2) constitute 10%–20% of breast cancers, and around 40% of patients with triple-negative breast cancer experience a recurrence within 3 years after surgery. Identifying those patients early can help doctors recruit them for clinical trials.

“We want to learn more about the different subtypes of breast cancer—what are the characteristics of cancers that make them resistant to chemotherapy?” Dr. Gonzalez-Angulo said. “Today, what I can offer a patient is participation in a clinical trial. Tomorrow, hopefully I can offer a patient participation in a clinical trial of the regimen that is most likely to be effective against that patient’s tumor.”

The study did not cover the time during which trastuzumab—the monoclonal antibody targeting HER2 that was approved by the U.S. Food and Drug Administration in 2005—was widely used in neoadjuvant therapy. Since its introduction, trastuzumab has greatly improved outcomes among patients with HER2-positive breast cancer. For example, patients with HER2-positive disease who received just an anthracycline or taxane before surgery had a pathological complete response rate of around 23%. The addition of trastuzumab has increased this response rate to more than 50%.

“HER2 positivity indicates a high risk for locoregional recurrence. By improving the drugs that we use and getting more complete responses, we get lower rates of locoregional recurrence,” Dr. Gonzalez-Angulo said.

Team effort

“The success of giving chemotherapy followed by breast-conserving therapy requires two things: one, that you pick your patients carefully, and two, that you work together as a team,” Dr. Buchholz said. Forgo one, and a physician could fail the patient.

“Breast cancers should be treated in a multidisciplinary fashion; you should talk to your colleagues before you make treatment decisions,” Dr. Gonzalez-Angulo said. “We never make decisions in isolation. Nobody says, ‘I’m a surgeon so I’m going to operate on her first,’ or, ‘I’m a medical oncologist and I’m going to give her chemotherapy first because that is what I do.’”

Dr. Mittendorf echoed Dr. Gonzalez-Angulo’s sentiments. “Instead of looking at a woman with breast cancer and saying, ‘I can do surgery on you, so let’s go to the operating room tomorrow,’ we really think about giving neoadjuvant chemotherapy as an opportunity to further interrogate the biology of the cancer.”

For more information, contact Dr. Elizabeth Mittendorf at 713-792-2362, Dr. Ana Gonzalez-Angulo at 713-563-0767, or Dr. Thomas Buchholz at 713-563-2335.

Other articles in OncoLog, April 2012 issue:

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