Use of Predictors of Recurrence to Plan Therapy for DCIS of the Breast

Introduction

"Her agony came from the fact that mastectomy would be curative and it was hard to turn that down. A lesser procedure, while preserving her breast and her femininity, offered her somewhat less chance for a complete cure--but exactly how much less was unknown. Perhaps only a small amount less. It didn't seem worth losing her breast for a few percentage points. Yet, maybe it was. It was the most difficult decision of her life. But medicine had failed her. The data upon which to base her judgment was weak, and we had shifted the burden of that judgment to her."[1]

That paragraph was written in 1991 about a woman with ductal carcinoma in situ (DCIS) of the breast and her arduous journey through the medical system as she searched for the "correct" treatment. There were a number of "correct" treatments then for her particular form of DCIS, but each was flawed in one way or another, confounding her thoughts and making her decision more difficult. But that was 1991. Today, we know much more about DCIS. But is the decision-making process any easier?

The results of the National Surgical Adjuvant Breast Project (NSABP) Protocol B-17 were published in 1993[2] and updated in 1995[3] and 1997[3a]. This prospective, randomized clinical trial was designed to resolve the controversy over the treatment of DCIS. More than 800 patients with DCIS excised with clear surgical margins were randomized to one of two treatments: excision only or excision plus radiation therapy. At 5 years, there was a statistically significant decrease in local recurrence of both DCIS and invasive breast cancer in patients treated with radiation therapy. These data led the NSABP to recommend postexcision radiation therapy for all patients with DCIS who chose to save their breasts--a recommendation that some consider too broad.[4,5]

The NSABP B-17 study was criticized for a number of reasons, including its definition of clear margins (which the NSABP defined as a tumor that is not transected), determination of size by central review of the pathology report, the absence of size measurements for more than 40% of cases, and, perhaps most important, the lack of pathologic subset analysis in the initial report.[4,5] In defense of the NSABP, the trial did exactly what it was designed to do; namely, it proved that radiation therapy was effective for patients with DCIS. It was not designed to answer the questions about patient subgroups that we ask today.

Consider the following two patients, both of whom merit radiation therapy based on the results of NSABP B-17. The first patient is a woman with a 12-mm low-grade lesion that has been widely excised with a minimum of 15-mm margins in all directions. Compare her with the second patient, a woman with a 35-mm high-grade lesion with DCIS approaching to within 0.2 mm of the inked margin but not involving it. According to the NSABP, both of these patients should be treated with radiation therapy.

At our facilities, based on data that will be presented below, the first patient would receive no additional therapy. Rather, she would be carefully followed with physical examination every 6 months and mammography every 6 to 12 months. The second patient would undergo a wide reexcision prior to making a final treatment decision. Significant residual disease approaching the new margins would earn a recommendation for mastectomy and immediate reconstruction; widely clear new margins with little or no residual DCIS would warrant consideration for radiation therapy.

Thus, despite the results of NSABP B-17, there continues to be debate regarding the DCIS decision-making process, which is not much clearer now than it was in 1991.

Numerous clinical, pathologic, and laboratory factors can aid clinicians and patients wrestling with the difficult treatment decision-making process. Our research has shown that nuclear grade, the presence of comedo-type necrosis (coagulative necrosis), tumor size, and margin width are all key factors in predicting local recurrence in patients with DCIS.[6-8] By using a combination of these factors, it may be possible to identify subgroups of patients who do not require irradiation, if breast conservation is elected; it also may be possible to identify patients whose recurrence rate is potentially so high, even with breast irradiation, that mastectomy is preferable.

Changing Patterns of Disease

Ductal carcinoma in situ is a biologically and histologically heterogeneous group of lesions.[9,10] With the appreciation and acceptance of this heterogeneity, DCIS has become confusing for both patients and physicians. Currently, it is not uncommon for DCIS patients to seek second, third, and even fourth opinions and to receive a diverse spectrum of advice ranging from biopsy only to wide excision, segmental resection, quadrant resection, mastectomy, or even bilateral mastectomy. As an adjunct to all these treatments except mastectomy, radiation therapy may be advised.

Patients seeking treatment advice will find physicians willing to support most of these options.[1] The second opinion-givers are usually oncologists specializing in medicine, surgery, or radiation therapy. Some patients, however, seek advice from their gynecologists, internists, or family practitioners. Many women also turn for counsel to family, friends, and other women who have had breast cancer, most of whom have had invasive disease.

Table 1 shows the changing nature of DCIS during the last decade. Before the widespread use of mammography, DCIS was diagnosed infrequently, representing less than 1% of all breast cancer cases.[11,12] Today, DCIS is common, accounting for approximately 12% to 15% of all newly diagnosed cases[13] and as many as 20% to 40% of cases at institutions that effectively utilize mammography.[14,15] In 1997, more than 36,000 new cases of DCIS are expected to be diagnosed in the United States.[16]

Previously, most patients with DCIS presented with clinical symptoms, such as a breast mass, bloody or serous nipple discharge, or Paget's disease and frequently had extensive disease.[11,17-19] Today, most lesions are smaller, nonpalpable, subclinical, and detected by mammography alone.

Until recently, the treatment for most patients with DCIS was mastectomy. Currently, many patients are being treated with breast preservation. Fifteen years ago, when mastectomy was common, reconstruction was infrequent and, if performed, was generally done as a delayed procedure with implants. Today, reconstruction for patients with DCIS treated by mastectomy is common and is usually done immediately, at the time of mastectomy, and often with autologous tissue.

In the past, when a mastectomy was performed, large amounts of skin were discarded. Now, it is considered safe to perform a skin-sparing mastectomy for DCIS.[20-23] We must keep in mind, however, that in patients with extensive disease, recurrences may develop after mastectomy (with or without reconstruction) in the scant residual breast tissue. The thicker the skin flaps, the more residual breast tissue is left behind and the more likely there is to be a recurrence.

In the past, there was no confusion. All breast cancers were considered the same and mastectomy was the only treatment. Today, we know that all breast cancers are different. There are many treatments and a great deal of confusion.

Factors Responsible for the Changes

These changes were brought about by numerous factors. The most important of these are increased utilization of mammography, improvements in mammographic technique, and the acceptance of breast-conservation therapy for invasive breast cancer.

Mammography--The acceptance of mammography not only changed the way we detect DCIS, it also altered the nature of the disease that we detected by allowing us to enter the neoplastic continuum at an earlier time. Every institution employing mammography has witnessed a relatively large increase in the number of small, mammographically detected cases of DCIS. This can be appreciated by charting the impact that mammography has had on the number and type of DCIS cases at one of our facilities, the Breast Center in Van Nuys, California.[24]

From 1979 to 1981, the Van Nuys group treated a total of only 15 patients with DCIS, an average of 5 per year. Only two lesions (13%) were nonpalpable. Two new mammography units and a full-time, experienced mammographer were added in 1982, and immediately the number of new DCIS cases increased to more than 30 per year, most of them nonpalpable. With the addition of a third mammography machine in 1987, almost 40 new cases per year were diagnosed. In 1994, a fourth mammography machine and a stereotactic biopsy unit were added. Analysis of the Van Nuys series through June 1996 (more than 500 patients) revealed that 81% of lesions were nonpalpable. If we consider only those lesions that were diagnosed after 1991, 92% were nonpalpable.

Breast Conservation--The second factor that affected how we think about DCIS was the acceptance of breast-conservation therapy (lumpectomy, axillary node dissection, and radiation therapy) for patients with invasive breast cancer. Until 1980, the treatment for most patients with any form of breast cancer was mastectomy. Since then, numerous prospective randomized trials have revealed that survival in patients with invasive breast cancer treated with lumpectomy and radiation therapy is equivalent to that in women who undergo mastectomy.[25-32] Based on these results, it was difficult to continue treating noninvasive disease with mastectomy while treating more aggressive invasive breast cancer with breast preservation.

Patients often ask the question, "You mean if I waited until my cancer was invasive, I could have saved my breast?" The answer is not that simple. Although there is clearly a relationship between DCIS and invasive breast cancer, the two entities are different heterogeneous groups of diseases with some overlap. It is extremely common to see both DCIS and invasive breast cancer within a single specimen. Authorities agree that DCIS is an obligate precursor to invasive breast cancer, but there is speculation that DCIS may be less amenable to control with irradiation. Thus, while patients with invasive breast cancers that are 4 cm or smaller and have little or no intraductal component can readily be treated by lumpectomy and radiation therapy, the same may not be true for patients with pure DCIS or for those with invasive breast cancer with an extensive intraductal component.

Nevertheless, current data suggest that many patients with DCIS can be successfully treated with breast preservation (with or without radiation therapy). In the sections that follow, we will show how easily available data can be used to predict which patients are more likely to suffer a recurrence after breast conservation. Knowing the probability of local recurrence can help simplify the complex treatment selection process.