By Christina Frangou

A new guideline on margins in breast cancer therapy establishes “no ink on tumor” as the standard for invasive cancer, saying it is associated with low rates of ipsilateral breast tumor recurrence (IBTR).

Wider margin widths do not significantly lower this risk, regardless of a woman’s age or biologic subtype, according to the guideline.

This new approach is expected to reduce re-excision rates, improve cosmetic outcomes and cut health care costs, according to the document issued by the Society of Surgical Oncology and the American Society for Radiation Oncology. the American Society for Clinical Oncology and the American Society of Breast Diseases also have endorsed the recommendations.

Currently, about one in four breast cancer patients in the United States undergoes re-excision after lumpectomy, and nearly half of these procedures are performed with the rationale of obtaining wider margins in women whose tumor cells do not touch the inked margin.

“Our hope is that this guideline will ultimately lead to significant reductions in the high re-excision rate for women with early-stage breast cancer undergoing breast-conserving surgery,” said Meena S. Moran, MD, associate professor of therapeutic radiology at Yale School of Medicine and Yale Cancer Center, New Haven, Conn., and co-chair of the consensus panel.

The professional organizations came together to examine the evidence on margins, in part, because of rising mastectomy rates in the United States, said panel co-chair Monica Morrow, MD, chief of breast surgery at Memorial Sloan-Kettering Cancer Center, New York City.

“We hear from patients that they don’t want to go back to the OR [operating room] for a second trip to have their margins excised. That’s not the only reason mastectomy rates are rising but it is a reason.”

No clinical trial has ever directly addressed the question of adequate margins. Instead, surgeons and radiation oncologists rely on indirect evidence, resulting in differing opinions over the definition of an adequate margin. Even at the same institution, surgeons and radiation oncologists often disagree on margin width.

To settle this question, an expert methodologist reviewed all available scientific evidence on margins. Leaders in surgical, radiation and medical oncology; pathology; and patient advocacy then met to review the findings and develop consensus.

In an interview, Dr. Moran said that the meta-analysis made it difficult to tease out the distinction between “no ink on tumor” and a margin of 1 mm. As a result, the panel took into account the current trends in IBTR and outcomes from randomized trials that demonstrated very low breast relapse rates. Together, these data strengthened the argument that “routine use of margins wider than no ink on tumor” will not necessarily further decrease these breast relapse rates, she said.

The full rationale behind the guideline is explained in an article in the February editions of the Annals of Surgical Oncology, the International Journal of Radiation Therapy Biology Physics and the Journal of Clinical Oncology (Epub ahead of print).

The authors stress that “no ink on tumor” should be the standard for all patients with stage I or II invasive breast cancer who were treated with whole-breast irradiation, including those who do not receive adjuvant systemic therapy, for all biologic subtypes and for patients with invasive lobular cancer. None of these situations is justification for wider margin widths, they said.

However, each patient’s care must be individualized, stressed Dr. Moran, and each case needs to be individualized to account for the patient’s risk for breast cancer relapse and how much a re-excision will decrease that risk.

“As a panel, we talked about [what we would do] if we had a very young woman with a triple-negative, high-grade tumor and no ink on tumor but had a portion of her tumor that closely approached the inked margin. Given that she’s a higher-risk, young patient without any targeted therapies or hormonal therapies available to her, it would be reasonable to consider a re-excision.”

A guideline issued last year by the American Society of Breast Surgeons “left a bit more wiggle room” about what to do with patients who had margins in the 1- to 2-mm range or focally involved margins, said Deanna Attai, MD, a surgeon in private practice at the Center for Breast Care, Inc., Burbank, Calif.

“If the margin is less than 2 mm, oftentimes I’m comfortable with it but that’s a case I take to the tumor board because I need to get the opinion of the other doctors who are going to be treating this patient as well, like the medical oncologists and radiation oncologists.

“We look at everything, and most of the time, my colleagues agree [not to re-excise a 1- to 2-mm margin] but sometimes we do have some discussion.” (See “Additional Expert Commentary.”)

One of the strengths of the new guideline is that professional organizations representing surgeons, radiation oncologists, pathologists and medical oncologists support the recommendations, she said.

“This is a recognition that all physicians who treat breast cancer need to shift their thinking and move into the modern era of breast cancer care in which wider is not better in terms of margins,” said Dr. Attai.

The panel found no evidence that increasing the margin width in younger patients would nullify their increased risks for relapse after breast-conserving therapy.

Patients with an extensive intraductal component (EIC) may have a large residual ductal carcinoma in situ (DCIS) burden after lumpectomy, the panel found. But, they added, no evidence exists in support of an association between increased risk for IBTR and EIC when margins are negative.

The panel also approved the “no ink on tumor” approach for women with invasive lobular carcinoma in situ (LCIS) but noted the significance of “pleomorphic LCIS at the margin is uncertain.”

Some early studies suggested that “larger margin width may have resulted in small reductions in local recurrence” but this is no longer relevant in the current setting of multimodality treatment, said the authors.

Improvements in drug therapy, such as the development of endocrine therapy, chemotherapy, pertuzumab and Herceptin, made the “no ink on tumor” recommendation possible, said Dr. Morrow.

“Drugs we give to prolong survival in breast cancer have the added benefit of reducing the risk for recurrence in the breast. So it makes sense to take advantage of this benefit, which wasn’t there when the first studies of lumpectomy were done,” said Dr. Morrow.

“Can we take advantage of this to decrease the extent of surgery? The answer to that is yes.”

The guidelines stress that positive margins, defined as ink on invasive cancer or DCIS, are associated with at least a twofold increase in IBTR. This risk is not nullified by delivery of a boost, delivery of systemic therapy or favorable biology.

The panel recommended that the choice of whole-breast radiation delivery technique, fractionation and boost dose not be dependent on the margin width.

Dr. Moran said she expects the guideline will be widely accepted by surgeons, radiation oncologists and medical oncologists.

“The key is that any guideline just provides a framework. The decision for re-excision must still be individualized for each patient. I believe that treating physicians understand this, and I hope they will welcome the guideline so that the routine use of a re-excision for all narrow—1 or 2 mm—margin widths is no longer justified,” she said.

The guideline is based on a meta-analysis and review of 33 research studies published between 1965 and 2013. The studies include 28,162 patients with stage I or II invasive breast cancer who were treated with whole-breast irradiation and a minimum median follow-up of four years. Patients treated with neoadjuvant chemotherapy or those with pure DCIS breast cancer were not included.

Additional Expert Commentary

Michael Goldfarb, MD
Program Director,
Department of Surgery,
Monmouth Medical Center,
Long Branch, New Jersey
Advisory Board Member

There are surgeons who have proceeded with a lot more wiggle room than 1- to 2-mm margins. We published our experience in The Breast Journal in 2006 (12:208-211). To date, there have been no local recurrences in those 100 patients. Of those patients, 13 required re-excision for close margins, and four were found to have additional tumor.

Statistics from the Jacqueline M. Wilentz Comprehensive Breast Center in Long Branch, N.J., from 1994 to 2012 revealed 739 women had breast-conservation surgery, and 108 had re-excisions with 22.2% additional tumor in the re-excised specimens. One of the 739 women had a local recurrence. In 65 of the women, a subsequent mastectomy rather than re-excision was performed because of extensive multiple margin issues with the first excision, and 46.7% were found to have additional tumor.

Because of the risk for additional tumor with close margins, we feel that re-excision is reasonable.