Ductal Carcinoma In Situ and Microinvasive Carcinoma
Kimberly J. Van Zee
Julia White
Monica Morrow
Jay R. Harris
INTRODUCTION
Ductal carcinoma in situ (DCIS), also known as intraductal carcinoma, is a noninvasive carcinoma. Historically, DCIS was an uncommon lesion that was routinely treated by mastectomy, and little attention was given to defining its natural history or exploring alternative local treatments. The widespread use of screening mammography has resulted in a significant increase in the rate of detection of DCIS (1) (Fig. 23-1). Although no prospective randomized trial has ever compared mastectomy with breast-conserving surgery for DCIS, the acceptance of breast-conserving therapy for the treatment of invasive carcinoma lead to its acceptance for the treatment of DCIS. Furthermore, four prospective randomized studies of radiation after breast-conserving surgery for DCIS have shown that breast cancer specific survival is excellent, with or without radiation (2, 3, 4 and 5). Therefore, there is a debate as to whether all DCIS should be regarded as early stage carcinoma and treated with either mastectomy or lumpectomy and irradiation, or whether excision alone can be used to treat some DCIS.
PRESENTATION
In 90% of cases, DCIS presents as an abnormal screening mammogram in an asymptomatic woman. Prior to widespread screening with mammography, DCIS presented with clinical symptoms and was an uncommon entity. In 1983, before screening was widely used, only 4,901 women were diagnosed with DCIS in the United States, accounting for 3.8% of all breast cancer (6). By 2013, approximately 64,640 new DCIS diagnoses will be made, representing approximately 20% to 25% of all new breast cancers (7). The SEER database has documented that the incidence of DCIS rose from 5.83 per 100,000 women in 1975 to 37.25 per 100,000 in 2009 (8). The increased incidence was observed in all age categories, with the greatest rise among women over 50 years of age (Fig. 23-1). The incidence of DCIS, like invasive breast cancer, is strongly related to age. DCIS is extremely uncommon before age 35 to 39; with incidences of less than 11 cases per 100,000. After that, the incidence rises steadily to a peak of 102 per 100,000 at ages 65 to 69. In contrast, invasive breast cancer incidence peaks at a later age (75-79 years) with incidence of 433.1 per 100,000 women (8, 9).
The increase in DCIS diagnosis has not been uniform across histological types (Fig. 23-2). An earlier analysis of the SEER database from 1980 to 2001 demonstrated that comedo histology rose in incidence from 1980 through 1995 but then stabilized or decreased slightly thereafter, while non-comedo histology continued to rise thorough the end of the study period (10). The age-adjusted incidence of DCIS was the highest among Caucasian women, followed by African-American and Asian-Pacific Islander women (11).
Microcalcifications are the predominant finding on screening mammography leading to a diagnosis of DCIS. As an example, in a study of 217 women 50 to 69 years of age with DCIS detected by mammography while participating in the Breast Cancer Screening program in Norway from 1995 through 2007, calcifications were present for 93%. On pathology review, calcifications were associated with grade 1 DCIS in 15%, grade 2 in 11%, and grade 3 in 74% (12). Calcification morphology on mammography was most frequently described as “fine pleomorphic.” In comparison, in a large surgical series from France of 909 cases of DCIS diagnosed from 1980 to 1999, 76.2% were detected by mammography without clinical symptoms, 12% had a palpable mass, and 12% presented with nipple discharge (13). Of
those with a palpable mass, 47.1% also had mammographic abnormalities. Microcalcification was the most common finding in 75.5%, with fine pleomorphic calcifications being the most frequently seen (40.4%), followed by amorphous or indistinct calcifications (35.9%). Fine pleomorphic and finelinear branching calcifications were significantly associated with the presence of grade 3 DCIS and necrosis (13).
those with a palpable mass, 47.1% also had mammographic abnormalities. Microcalcification was the most common finding in 75.5%, with fine pleomorphic calcifications being the most frequently seen (40.4%), followed by amorphous or indistinct calcifications (35.9%). Fine pleomorphic and finelinear branching calcifications were significantly associated with the presence of grade 3 DCIS and necrosis (13).
 FIGURE 23-1 SEER Incidence rates 1975 to 2009 for in situ versus invasive breast cancer by age, all races. (From Howlader N, Noone AM, Krapcho M, et al., eds. SEER Cancer Statistics Review, 1975-2010, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2010/, based on November 2012 SEER data submission, posted to the SEER web site, April 2013.) |
DCIS that is diagnosed with a palpable mass or nipple discharge is more likely to be extensive disease. Examination of 50 mastectomy specimens in a population of DCIS patients, of whom 58% were detected with mammography and 42% with clinical mass or nipple symptoms, revealed that presentation with a palpable mass, nipple discharge, or as Paget’s disease was accompanied by a greater incidence of multicentricity and/or microinvasion than was DCIS detected by mammography (14). In addition, patients with comedo necrosis or micropapillary architecture were more likely to be multicentric than other histologic subtypes. More recent studies suggest that, in most cases, true multicentricity in DCIS is rare. Holland and Hendricks studied 119 mastectomy specimens containing DCIS by a subgross pathologic-mammographic technique (15). In all but one case, the tumor was confined to a single “segment” of the breast. Clearcut multicentric distribution (defined in this study as foci of DCIS separated by 4 cm or more of uninvolved breast tissue) was seen in only one patient. Faverly et al., using stereomicroscopic three-dimensional analysis to define the growth pattern of DCIS in the mammary duct system, studied 60 mastectomy specimens containing DCIS (16). There was continuous growth pattern in the ducts for 50% and a discontinuous pattern in 50%, characterized by uninvolved breast tissue “gaps” between foci of DCIS. In most instances, these gaps were small (< 5 mm in 82% of cases). The likelihood of finding such gaps was related to the DCIS
differentiation: 90% of poorly differentiated cases grew in a continuous manner without gaps, while 45% and only 30% of intermediate and well-differentiated lesions, respectively, were continuous. The findings in these two studies indicate that, in most cases, DCIS involves the breast in a segmental distribution, and truly multicentric disease is uncommon.
differentiation: 90% of poorly differentiated cases grew in a continuous manner without gaps, while 45% and only 30% of intermediate and well-differentiated lesions, respectively, were continuous. The findings in these two studies indicate that, in most cases, DCIS involves the breast in a segmental distribution, and truly multicentric disease is uncommon.
 FIGURE 23-2 Incidence of in situ carcinoma (per 100,000 women) by different histological types among women ages ≥ 30 years, 1980 to 2001. (▪ DCIS overall, • non-comedo DCIS, ▲ comedo DCIS, ♦ LCIS. From Li CI, Daling JR, Malone KE, et al. Age-Specific Incidence Rates of In situ Breast Carcinomas by Histologic Type, 1980 to 2001. Cancer Epidemiol Biomarkers Prev. American Association for Cancer Research, 2005). |
Mammography is the established method for detection and evaluation of extent of disease, but MRI is being increasingly studied for its clinical utility in DCIS diagnosis (17). Historically, MRI was considered a poor imaging tool to assess DCIS. The adoption of higher spatial resolution techniques and diagnostic criteria that are different than those used for invasive cancer has led to improved detection of DCIS by MRI. In the International Breast MRI Consortium study of patients with suspicious mammographic or clinical findings, the sensitivity of MRI for the detection of DCIS was 73%; significantly lower than the 91% observed for invasive cancer (18). The American College of Radiology Imaging Network (ACRIN) compared the diagnostic accuracy of mammography, clinical examination, US, and MRI prospectively in the preoperative assessment of 171 malignant foci, 38 of which were DCIS, in 121 breasts from 111 women. MR imaging identified 34 of 38 (89%) DCIS foci, which was significantly more than was detected with either US (p < .001) or mammography (p < .01) (19). These results were further supported by Kuhl et al. (20), who reported on 167 cases of DCIS that had, at some point during their workup, undergone both mammography and MRI. All imaging was re-read centrally and MRI studies were read blinded to the mammogram findings. MRI detected 92% of cases as compared to 56% by mammography (p < .0001). Of the 89 cases of high-grade DCIS, 48% were diagnosed by MRI but missed by mammography. Other studies have similarly demonstrated a 70% to 90% MRI sensitivity for DCIS detection (21). Additional investigation to clarify the clinical role of MRI for diagnosing DCIS and its prognostic implication are needed.
NATURAL HISTORY
There is significant evidence based on epidemiology, clinical observation, and growing numbers of genetic, molecular, and epigenetic studies that DCIS is a precursor lesion for invasive cancer. However, predicting which individual DCIS case will progress to invasive breast cancer if left untreated remains indefinable.
Epidemiologic studies that examine risk factors for DCIS show that they are remarkably similar to those for invasive breast cancer, including a family history of breast cancer, nulliparity, older age at first childbirth, and breast density (9). Clinical observation of DCIS progression to invasive cancer is limited as surgical resection is done once a diagnosis of DCIS is made. However, clinical follow-up from benign breast biopsies that received no additional intervention but on re-review many years later were diagnosed as DCIS offers some insight regarding clinical progression. Sanders et al. (22) identified 28 cases of small, low-grade, non-comedo DCIS during a review of 11,760 consecutive breast biopsies performed from 1950 through 1968. With a median followup of 28 years, 11 of 28 women (39%) developed ipsilateral invasive breast carcinoma, all in the same quadrant from which the original biopsy was taken. Seven (64%) of the 11 recurrences developed within 10 years, and 5 (45%) of the 11 (18% of all 28 cases) died of metastatic disease. Eusebi et al. reported on 80 cases of DCIS retrospectively diagnosed out of 9,446 breast biopsies done between 1964 and 1976, and with a median follow-up of 17.5 years. Pure “clinging carcinoma” (CC) was diagnosed in 41; 9 with pleomorphic nuclei (consistent with DCIS) and 32 with monomorphic nuclei which is currently considered flat epithelial atypia. Five (12%) developed an ipsilateral breast cancer: 2 of the 9 with pleomorphic nuclei developed ipsilateral invasive carcinoma, and 2 of the 32 with monomorphic nuclei developed DCIS. Of the 30 cases of CC associated with cribriform DCIS, LCIS, or both, 5 (17%) had an ipsilateral invasive recurrence. Two of 7 cases with cribriform DCIS developed an ipsilateral DCIS recurrence, and 2 of 2 cases with comedo DCIS developed an invasive recurrence (23). In a similar study, Rosen et al. (24), described 30 women with untreated DCIS; complete follow-up was available only for 15. Ipsilateral invasive breast cancers occurred in 7 of the 15 (53%) at a mean of 9.7 years after the diagnosis of DCIS. More recently, Collins et al. (25), found 13 cases of DCIS (0.7%) out of 1,877 breast biopsies performed from 1973 through 1991 on the Nurses’ Health Study. Nuclear grading of the 13 cases revealed 6 to be intermediate, and 3 were high nuclear grade. A total of 10 cases recurred (77%); 6 (46%) developed invasive breast cancer at a mean of 9 years, and 4 (31%) developed DCIS at a mean of 3.75 years after the initial biopsy was performed.
The clear limitation of these studies is that the completeness of excision by the original biopsy is unknown; however, as a whole, they demonstrate that a significant portion of both low- and high-grade DCIS can progress to invasive breast cancer, supporting its role as a precursor.
Another source of indirect clinical evidence of DCIS as a precursor comes from autopsy studies. Alpers and Wellings (26) assessed a series of 185 randomly selected breasts from 101 women examined by a subgross sampling technique. One or more foci of DCIS were found in only 11 cases (6%). The lowest prevalence was noted in the oldest women: 3 of 56 (5%) in women younger than age 49; 7 of 70 women (10%) in women ages 50 through 69; and in 1 of 59 women (2%) older than 70 years were found. In a study with similar methodology, Bartow et al. (27), performed pathologic examination of the breast on 519 autopsied women 14 years of age or older without clinical evidence of breast cancer. Only one case of DCIS was identified in a 40 year old; five occult invasive carcinomas were found in women ages 45 to 87. These findings suggest that DCIS progresses to clinically evident breast cancer given its very low prevalence at autopsy, particularly in the oldest cohort of women.
There has been considerable research over the last several years in understanding the gene expression changes that occur in DCIS relative to what is known in invasive breast cancer. Over the past decade, the successful combination of highly specific tissue microdissection technologies with advanced high-throughput genomic, gene-expression, and proteomic technologies has enabled a better understanding of the pre-invasive stages of breast cancer progression (28). It is now acknowledged that significant genomic and gene expression parallels exist between the pre-invasive and invasive stages of breast cancer.
Several studies have examined genetic changes in DCIS, i.e., loss of heterozygosity (LOH), at genetic loci (typically considered to be approximate locations of inactivated tumor suppressor genes) known to exhibit high rates of loss in invasive breast cancer. These showed that the frequency of chromosomal losses, specifically regions 16q and 17p, in ADH is similar to that observed in DCIS and invasive carcinoma (28). O’Connell and colleagues examined 399 pre-malignant breast lesions, studying 15 genetic loci known to show high rates of LOH in invasive breast cancer (29). In breasts without invasive breast cancer, they found at least one locus of LOH in 42% of ADH, 70% of non-comedo DCIS, and 79% of comedo DCIS. Among specimens harvested from cancerous breasts, LOH was shared with the synchronous cancer in at least one locus in 45% of ADH, 77% of non-comedo
DCIS, and 80% of comedo DCIS lesions. This observation that the majority of both comedo and non-comedo DCIS share their LOH phenotypes with synchronous invasive breast cancer supports the concept that DCIS is a direct precursor of invasive breast cancer.
DCIS, and 80% of comedo DCIS lesions. This observation that the majority of both comedo and non-comedo DCIS share their LOH phenotypes with synchronous invasive breast cancer supports the concept that DCIS is a direct precursor of invasive breast cancer.
Ma and associates used laser capture microdissection and DNA microarrays to generate in situ gene expression profiles in 36 breast tissue specimens that exhibited one or more lesions of ADH, DCIS, and invasive carcinoma (30). No consistent gene expression alterations unique to ADH, DCIS or invasive carcinoma were found; instead, the greatest alterations in gene expression were seen by histological grades. Similar to what has been observed with invasive breast cancer, distinct gene-expression signatures are present in low- and high-grade DCIS lesions, and are consistent with genetic alterations and phenotypes seen in comparable grade invasive cancer. These data suggest that low-grade DCIS progresses to low-grade invasive and high-grade DCIS to high-grade invasive, with intermediate-grade DCIS representing intermediary behaviors.
There has been increasing focus on the DCIS microenvironment for identification of promoters of tumor progression. Recent gene-expression and epigenetic data strongly suggest that the stromal and myoepithelial microenvironment of preinvasive breast cancer actively participates in the transition from pre-invasive to invasive disease (28). Allinen et al. (31) developed a purification procedure that allows the isolation of pure cell populations from normal breast tissue, DCIS, and invasive carcinoma. They demonstrated that genes coding for CXCL14 and CXCL12 chemokines were overexpressed in DCIS myoepithelial cells and myofibroblasts, respectively, compared to normal breast tissue. These chemokines can bind to receptors on adjacent epithelial cells and enhance their proliferation, migration, and invasion. Thus, chemokines may have a part in the transition from DCIS to invasive breast cancer by acting as paracrine factors. This illustrates how signaling from the DCIS stromal and myoepithelial microenvironment may play an important role in tumorigenesis.
These genetic and molecular studies give further evidence that ductal pre-invasive stages (ADH and DCIS) are non-obligate precursors to invasive disease with variable clinical behavior.
TREATMENT
The uncertainty regarding the natural history of DCIS has resulted in a wide range of local treatment practices, from excision alone to mastectomy. There is now a significant body of mature data from prospective, randomized trials in well-characterized populations of women with DCIS that provides information about the risks of local recurrence and death after treatment with lumpectomy alone, and lumpectomy and radiation therapy (RT). Clinical trials have also evaluated the benefit of endocrine therapy in patients with DCIS. There are no prospective studies evaluating mastectomy or comparing it to breast-conserving surgery.
TABLE 23-1 Recurrences after Mastectomy for DCIS (recent series with >100 cases and >5 years follow-up) | ||||||||||||||||||||||||||||||||||||||||||
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Mastectomy
Theoretically, mastectomy should be 100% curative for pure DCIS. While no prospective studies of mastectomy for DCIS exist, large (at least 100 women) retrospective series, with at least 5 years of follow-up, report actual local recurrence rates in the 1% to 3% range (Table 23-1). A meta-analysis of 1,574 mastectomies reported a recurrence rate of 1.4% (95% confidence interval [CI], 0.7-2.1) at an average follow-up of 80 months (32). Recurrence after mastectomy is usually invasive carcinoma and may present as either local recurrence or distant metastases without evidence of local recurrence. Breast cancer-specific survival rates at 10 years after mastectomy for DCIS are ≥ 98% (33, 34).
Skin-sparing mastectomy allows preservation of the native skin envelope, resulting in improved cosmesis with immediate reconstruction. At a mean follow-up of 82 months, local recurrence occurred in 3.1% of 223 consecutive patients undergoing skin-sparing mastectomy for DCIS (35). Others have reported local recurrence rates from 0% to 4% at 3.5 to 10 years of follow-up (35).
In an effort to further reduce the psychological and cosmetic impact of mastectomy, nipple-sparing mastectomy has been recently explored. To date, limited local recurrence data are available. In 158 patients undergoing mastectomy with intraoperative radiation of the nipple-areola complex for ductal intraepithelial neoplasia, Petit et al. reported a 5-year local recurrence rate of 5%, with a nipple-areolar complex recurrence rate of 2.9% (36). A prospective series of 33 women undergoing 54 nipple-sparing mastectomies from the University of Texas MD Anderson Cancer Center (MDACC) reported a 30% complication rate in the nipple-areola complex, 11% in the skin flaps, and the need to remove the nipple-areolar complex due to DCIS involvement in 12% (37). Cosmetic outcome was acceptable (as judged by plastic surgeons) in 73% of breasts and 56% of nipple-areolar complexes, with most (67%) being laterally displaced.
Treatment failure after mastectomy for DCIS may be due to unsampled or unrecognized invasive carcinoma that results in local recurrence or distant metastases, or it may be due to incomplete removal of breast tissue. Residual breast tissue may harbor DCIS; it also has the potential for development of a new carcinoma that would be manifested as a “local recurrence.”
TABLE 23-2 Radiotherapy Effect: Results of the Phase III Randomized Control Trials | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Mastectomy is a highly effective treatment for DCIS, but it is a radical approach to a lesion that may not progress to invasive carcinoma during the patient’s lifetime. It seems somewhat paradoxical that a woman with a palpable invasive carcinoma should be able to preserve her breast, whereas the “reward” for screening and early detection of DCIS is a mastectomy. The acceptance of breast-conserving therapy for the treatment of invasive carcinoma led to its use as a treatment for DCIS. However, no randomized trial has ever compared the treatment of DCIS by mastectomy with treatment by breast-conserving approaches, and no such trial is likely to occur. In some cases, the assumption has been made that because these two treatments result in equivalent survival for patients with invasive carcinoma, the same is true for patients with DCIS. This assumption is flawed because of the fundamental difference in the risk of metastatic disease for patients with invasive carcinoma and those with DCIS. In DCIS, unlike invasive cancer, the risk of metastases at diagnosis is negligible, while an invasive local recurrence carries with it the potential risk of breast cancer mortality. Therefore, the incidence of invasive recurrence and the results of salvage therapy should determine the suitability of breast-conserving approaches as a treatment for DCIS.
TABLE 23-3 Patient and Treatment Variables in the Phase III Randomized Control Trials Evaluating Radiotherapy Effect Post Lumpectomy for DCIS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Breast-Conserving Surgery and Radiation Therapy
Five randomized control trials have evaluated the extent of benefit from breast radiotherapy in reducing cancer recurrence following complete excision for DCIS (Table 23-2). The first of these was the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-17 clinical trial that, from 1985 through 1990, enrolled 818 women who had undergone lumpectomy for DCIS with microscopically clear margins and were randomized to observation post excision versus whole breast radiotherapy. The characteristics of the DCIS population accrued are seen in (Table 23-3). At 42 months median follow-up, a 59%
average annual reduction in ipsilateral breast cancer events was demonstrated with the addition of radiotherapy after lumpectomy (38) that persisted at 8 (39)and 12 years median follow-up (40). The most recent analysis done after 17.25 years median follow-up demonstrates a sustained benefit of breast radiotherapy with a 52% relative reduction in the risk of invasive ipsilateral breast cancer recurrence (hazard ratio [HR], 0.48; 95% CI, 0.33-0.69; p < .001) and a 47% reduction in the risk of DCIS ipsilateral in-breast recurrence (HR, 0.53; 95% CI, 0.35-0.8; p < .001) compared to those randomized to lumpectomy alone. The same percentage of women developed contralateral breast cancer in the lumpectomy-alone group (10.3%) and in the group that received radiotherapy (10.2%). Likewise, overall and breast cancer mortality did not differ for the lumpectomy-alone versus the breast radiotherapy group (2).
average annual reduction in ipsilateral breast cancer events was demonstrated with the addition of radiotherapy after lumpectomy (38) that persisted at 8 (39)and 12 years median follow-up (40). The most recent analysis done after 17.25 years median follow-up demonstrates a sustained benefit of breast radiotherapy with a 52% relative reduction in the risk of invasive ipsilateral breast cancer recurrence (hazard ratio [HR], 0.48; 95% CI, 0.33-0.69; p < .001) and a 47% reduction in the risk of DCIS ipsilateral in-breast recurrence (HR, 0.53; 95% CI, 0.35-0.8; p < .001) compared to those randomized to lumpectomy alone. The same percentage of women developed contralateral breast cancer in the lumpectomy-alone group (10.3%) and in the group that received radiotherapy (10.2%). Likewise, overall and breast cancer mortality did not differ for the lumpectomy-alone versus the breast radiotherapy group (2).
The European Organization for Research and Treatment of Cancer (EORTC) conducted a similarly designed randomized clinical trial investigating the role of radiotherapy after lumpectomy for DCIS ≤ 5 cm in size (3, 41). It enrolled 1,010 women between 1986 and 1996. Microscopically clear resection margins were not stipulated for eligibility in this trial. In comparison to NSABP B-17 (Table 23-3), this population had less screen-detected DCIS (71%) and fewer excisions with negative surgical margins (78%). The first results reported at a median of 4.25 years demonstrated a 43% relative reduction in cancer recurrence in the treated breast with the addition of radiotherapy; 16% for observation versus 9% with treatment (p = .005) (41). Ten-year outcomes from the EORTC 10853 trial demonstrated a sustained 47% relative reduction in ipsilateral local recurrence (3). An approximately equal reduction in DCIS and invasive cancer recurrences was seen. There was no difference at 10 years by treatment group in the rate of contralateral breast cancer, distant metastases, breast cancer deaths, and overall survival.
The Swedish Breast Cancer group, from 1987-1999, enrolled 1,067 women who had undergone lumpectomy for DCIS occupying a quadrant or less of the breast into the SweDCIS trial. Women were randomized to observation versus postoperative whole breast radiotherapy. Microscopically clear surgical margins were not required. In 97%, specimen radiography was done at the time of lumpectomy. The patient population was similar to that enrolled on the EORTC 10853 clinical trial (Table 23-3). At 5 years a 67% relative reduction in local recurrence in the treated breast was seen: 22% in the observation group versus 7% in the radiotherapy group (p < .0001) (42). At a mean of 8 years of follow-up, a sustained 60% reduction in local recurrence (corresponding RR of 0.40 (95% CI, 0.30-0.54) was seen with the addition of radiotherapy. There were similar reductions in risk for ipsilateral invasive and DCIS recurrences (Table 23-2) (5).
The United Kingdom, Australia, and New Zealand (UK/ANZ) DCIS Trial accrued 1,701 women with DCIS detected in the National Breast Screening Program who had undergone lumpectomy with cancer-free surgical margins between 1990 and 1998 (4, 43). The trial used a 2 × 2 factorial design to assess radiotherapy, tamoxifen, or both in patients with completely excised DCIS. Patients could elect to either enter into the fourway randomization or one of two separate two-way randomizations. Among the various randomization schemes, 1,030 patients were randomized to radiotherapy or observation after lumpectomy. This population reflects its origins from the screening program, so most (91%) are 50 years or older, and given the trial design, 54% received tamoxifen (Table 23-3). At a median follow-up of 5.25 years, radiotherapy was associated with a 64% relative and 8.9% absolute reduction in risk for all ipsilateral events (13.7% in the control group and 4.8% in the irradiated group, p < .0001) (43). A durable effect of radiotherapy is seen at 12.7 years median follow-up with a 68% relative and 12.3% absolute reduction in ipsilateral cancer recurrences (from 19.4% in the control versus 7.1% with irradiation; HR, 0.32; 95% CI, 0.22-0.47; p < .0001) (Table 23-2) (4).
A meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) provides a concise overview of radiotherapy effect following lumpectomy for DCIS (44). A total of 3,729 women were eligible for analysis from the NSABP B-17, EORTC 10953, SweDCIS, and UK/ANZ trials, with a median follow-up of 8.9 years. Radiotherapy approximately halved the rate of ipsilateral breast events (rate ratio 0.46; standard error [SE], 0.05; 2 p < .00001) with no evidence of heterogeneity between the trials in the proportional reduction. At 5 years after randomization, the absolute reduction in risk was 10.5% (SE 1.2%, 7.6% vs. 18.1%) and at 10 years after, it was 15.2% (SE 1.6%, 12.9% vs. 28.1%). Radiotherapy was effective in reducing ipsilateral breast events regardless of whether the woman was younger or older than 50 years at diagnosis, local excision or sector resection had been performed, and tamoxifen or not was given (tamoxifen only given on the UK/ANZ trial). Furthermore, radiotherapy was effective in reducing ipsilateral breast events regardless of the mode of detection, surgical margin status, focality, histologic or nuclear grade, or the presence of comedo necrosis or comedo/solid architecture. Radiotherapy resulted in a larger proportional reduction in the rate of ipsilateral breast recurrence for women older than 50 years of age than for younger women (rate ratios: age < 50 years 0.69, SE 0.12; ≥ 50 years 0.38, SE 0.06; 2p = 0.0004 for the difference between these proportional reductions). The proportional reduction did not differ significantly according to any other factor. There was no significant difference in the meta-analysis for breast cancer or overall mortality between treatment arms. The 10-year cumulative risk of breast cancer mortality was 4.1% for the radiotherapy groups and 3.7% for observation post lumpectomy (44). Importantly, there was no significant difference in heart disease deaths in those irradiated versus observed.
Within the EBCTCG analysis a “low-risk” group was sought in which the absolute risk of ipsilateral breast events was so low that the addition of radiotherapy would provide little absolute gain. There were 297 such cases of DCIS identified that were low-grade, less than 20 mm in size, and had negative surgical margins. Among them, the 10-year risk of an ipsilateral event in those allocated to lumpectomy alone was substantial at 30.1%, and even with this relatively small number of women, the effect of radiotherapy was highly significant (rate ratio 0.48; SE 0.17; 2p = 0.002), with a 10-year absolute gain of 18.0% (SE, 5.5%) (44).
Recently, the Radiation Therapy Oncology Group (RTOG) reported the results from its RTOG 9804 clinical trial for “Good Risk” DCIS post lumpectomy, randomizing patients to observation versus breast radiotherapy (45). The results from prior randomized trials likely reflect the inclusion of DCIS cases with higher risk features: high histologic and/or nuclear grade, involved surgical margins in some cases, larger tumor sizes, and limited tamoxifen use. RTOG 9804 sought to identify and determine radiotherapy benefit after lumpectomy for DCIS patients who were expected to have a low risk of ipsilateral breast recurrence. The study opened in 1999 and was targeted to accrue 1,790 women, but closed because of poor accrual in 2006 having randomized 636 patients. RTOG 9804 enrolled women with smaller lesions, all of which were low- or intermediate-grade DCIS. The study had a much higher rate of adjuvant tamoxifen use (62%) (Table 23-3). After a median follow-up of 7.2 years there have been 19 in-breast recurrences (42% invasive, 58% DCIS) in the observation arm (7-year rate, 6.7%) and 2 (50% invasive, 50% DCIS) in the radiotherapy group (7-year rate, 0.9%) for a hazard ratio of 0.11 (95% CI, 0.03-0.47; p = .0003)
(45). The eligibility criteria for RTOG 9804 are similar to the low/intermediate-grade stratum of the Eastern Cooperative Oncology Group (ECOG) single arm registration-observation study for DCIS post lumpectomy discussed elsewhere (46). For the low/intermediate-grade stratum on ECOG 5194, the 7-year rate of ipsilateral breast recurrence is 10.5% (46). This discrepancy in 7-year rates of ipsilateral breast recurrence between the two trials may be influenced by the tamoxifen use that was double in the RTOG 9804 (62%) population compared to the ECOG 5194 low/intermediate-grade stratum (31%). Additional follow-up of RTOG 9804 is needed to ensure endurance of the results given its incomplete accrual and the longer time to failure that has been reported for lower-grade DCIS; however, it appears that, based on standard clinical-pathologic criteria, a cohort of DCIS could be identified with a low rate of in-breast recurrence at 7 years without radiotherapy (but with tamoxifen in most). However, even in this low-risk group, the addition of radiotherapy reduced the in-breast recurrence rate by a relative 89% and an absolute 5.8%.
(45). The eligibility criteria for RTOG 9804 are similar to the low/intermediate-grade stratum of the Eastern Cooperative Oncology Group (ECOG) single arm registration-observation study for DCIS post lumpectomy discussed elsewhere (46). For the low/intermediate-grade stratum on ECOG 5194, the 7-year rate of ipsilateral breast recurrence is 10.5% (46). This discrepancy in 7-year rates of ipsilateral breast recurrence between the two trials may be influenced by the tamoxifen use that was double in the RTOG 9804 (62%) population compared to the ECOG 5194 low/intermediate-grade stratum (31%). Additional follow-up of RTOG 9804 is needed to ensure endurance of the results given its incomplete accrual and the longer time to failure that has been reported for lower-grade DCIS; however, it appears that, based on standard clinical-pathologic criteria, a cohort of DCIS could be identified with a low rate of in-breast recurrence at 7 years without radiotherapy (but with tamoxifen in most). However, even in this low-risk group, the addition of radiotherapy reduced the in-breast recurrence rate by a relative 89% and an absolute 5.8%.
TABLE 23-4 Outcome for DCIS Treated with Lumpectomy and Whole Breast Radiotherapy from Single- and Multi-Institution Experiences | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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In addition to the randomized control trials, there have been numerous institutional experiences with lumpectomy and RT for DCIS demonstrating similar in-breast cancer event rates, acceptable toxicity, good cosmetic results, and excellent breast cancer-specific survival (Table 23-4).
TABLE 23-5 Breast Radiotherapy Delivered in Randomized Control Trials Evaluating Benefit after Lumpectomy for DCIS | ||||||||||||||||||||||||||||||||||||||||||||||
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Radiation Therapy Methods
The radiotherapy delivered post lumpectomy was fairly consistent across the 5 randomized trials, and in all cases the entire breast was irradiated (Table 23-5). The most common radiotherapy regimen was to deliver 50 Gy to the whole breast over 25 treatments or fractions of 2 Gy daily over a treatment period of 5 weeks. Boost or additional dose to the lumpectomy cavity vicinity was not recommended. Given that radiotherapy after lumpectomy for DCIS does not give a survival benefit, there has been understandable concern regarding the known excess risk for cardiovascular mortality associated with breast radiotherapy in the past (47). Methods of breast radiotherapy post lumpectomy that avoid/minimize cardiac irradiation for left-sided DCIS cases are imperative. One of the important findings of the EBCTCG meta-analysis is that there was no statistically significant excess heart disease mortality for those given breast radiotherapy after lumpectomy (44). There were 26/1878 (1.38%) heart disease deaths for those allocated to post lumpectomy radiotherapy versus 29/1851 (1.57%) for lumpectomy alone with 8.9 years median follow-up.
Shortened whole breast irradiation (WBI) treatment courses that are achieved with hypofractionation, or the delivery of larger daily radiation doses of 2.67 Gy to a total of 40 or 42.67 Gy with 15 or 16 treatments over approximately 3 weeks time, are being increasingly used after excision for DCIS. New
York University reported a Phase I/II single arm prospective trial in 59 patients using hypofractionated WBI of 42 Gy in 15 fractions of 2.8 Gy for treatment of DCIS (48). At a median follow-up of 36 months, there were no grade 3 radiation toxicities early or late, 91% of women reported a good-excellent cosmetic outcome, and no in-breast recurrences were reported. The University of Toronto reported their retrospective analysis of 266 women with DCIS who received either standard fractionated (104 cases) or hypofractionated (162 cases) WBI post lumpectomy. With a median follow-up of 3.76 years, the actuarial risk of ipsilateral breast recurrence at 4 years was 7% with hypofractionated WBI and 6% with the conventional schedule (p = .9) (49). The American Society for Radiation Oncology (ASTRO) evidence-based guideline on Fractionation for Whole Breast Irradiation concluded that data were insufficient so far to recommend for or against hypofractionated WBI post lumpectomy for women with DCIS (50).
York University reported a Phase I/II single arm prospective trial in 59 patients using hypofractionated WBI of 42 Gy in 15 fractions of 2.8 Gy for treatment of DCIS (48). At a median follow-up of 36 months, there were no grade 3 radiation toxicities early or late, 91% of women reported a good-excellent cosmetic outcome, and no in-breast recurrences were reported. The University of Toronto reported their retrospective analysis of 266 women with DCIS who received either standard fractionated (104 cases) or hypofractionated (162 cases) WBI post lumpectomy. With a median follow-up of 3.76 years, the actuarial risk of ipsilateral breast recurrence at 4 years was 7% with hypofractionated WBI and 6% with the conventional schedule (p = .9) (49). The American Society for Radiation Oncology (ASTRO) evidence-based guideline on Fractionation for Whole Breast Irradiation concluded that data were insufficient so far to recommend for or against hypofractionated WBI post lumpectomy for women with DCIS (50).
The potential benefit of adding a boost, or supplemental radiation dose focused on the lumpectomy cavity vicinity only following WBI, remains an area of controversy for radiation management of DCIS. Boost was not part of protocol therapy in any of the 5 randomized clinical trials (Table 23-5). In the treatment of invasive breast cancer with breast-conserving therapy, the EORTC 22881-10882 clinical trial demonstrated that the use of a boost dose to the lumpectomy cavity vicinity after WBI resulted in a 41% relative and 4% absolute reduction in local recurrence at 10 years (p = .0001) (51). Given these data for invasive disease, the practice of adding a boost has been adopted following WBI for DCIS. This is evident in the 1,003 pooled cases from 10 institutions treated with breast radiotherapy post lumpectomy between 1973 and 1995, where a boost was delivered in 72% (52). In that study, there was not a significant difference in local recurrence for those that received less than 60 Gy (9%) versus those who received more (11%) (p = .91) at a median of 8.9 years follow-up. The use of a boost for DCIS is supported by a retrospective pooled analysis by the Rare Cancer Network that studied 373 young women (age < 45 years) with DCIS across 18 institutions who all underwent lumpectomy and then were either observed or received WBI with or without a boost (53). After a median follow-up of 6 years, the 10-year local recurrence rate reported for no radiotherapy was 34%; 28% for WBI without boost; and 14% for WBI with boost (p < .0001). However, another retrospective analysis from the British Columbia Cancer Agency database found no benefit of boost in 995 cases of DCIS treated with breast-conserving therapy with a 9.3 year median follow-up. In this analysis, the rate of local recurrence at 10 years was 13% in 475 cases without radiotherapy, 6% in 378 cases with WBI without boost, and 9% in 144 cases of WBI with boost (p = .065) (54). A secondary unplanned analysis examining the benefit of the “boost” was done on the NSABP B-24 clinical trial that examined tamoxifen effect after lumpectomy and WBI for DCIS (55). In this sub-analysis of 1,569 women enrolled on NSABP B24 with a 14.1-year median follow-up, it was documented that the 692 women who received a boost after WBI (38%) were more likely to have had involved margins and the presence of comedo necrosis than the 877 who were not boosted. The use of a boost did not result in a reduction in the rate of ipsilateral breast recurrence: 14.3% without boost and 13.8% with boost (55). The use of boost in the EORTC 22881-10882 clinical trial was accompanied by a significant increase in severe fibrosis and worsening of the cosmetic outcome (51). In the setting of DCIS, it is important to weigh the local control benefit of using a boost against the potential for adverse toxicity and cosmetic outcomes. These unanswered questions regarding radiotherapy fractionation and boost for DCIS are being addressed in a phase III randomized trial (NCT00470236) by the Trans-Tasman Radiation Oncology Group (TROG), “Radiation Doses and Fractionation Schedules in Non-low Risk Ductal Carcinoma in Situ (DCIS) of the Breast.” This trial opened in 2007 and is targeted to accrue 1,600 women.
Early reports of accelerated partial breast irradiation (APBI) that focuses a short course (5-10 treatments over 5-8 days) of post excision radiotherapy solely to the vicinity of the lumpectomy cavity for treatment of DCIS have been favorable. Twelve institutions participated in a phase II clinical study using the MammoSite® brachytherapy for APBI for DCIS post lumpectomy, enrolling 133 patients from 2003-2006 (56). With a mean follow-up period of 9.5 months, there were 2 DCIS failures in the ipsilateral breast. William Beaumont Hospital reported retrospectively on 99 cases of DCIS treated with post lumpectomy APBI (57), and with a mean follow-up of 3 years, there has been 1 ipsilateral breast recurrence for a reported 5-year rate of 1.4%. There are 194 cases of DCIS in the American Society of Breast Surgeons registry of 1,449 cases from 97 institutions of early-stage breast cancer treated with APBI using the MammoSite® brachytherapy device (58). The most recent update after a median follow-up of 4.5 years reported 6 patients (3.1%) who had an ipsilateral breast recurrence, for a 5-year actuarial local recurrence rate of 3.39%. Acknowledging that these early results in DCIS are promising, but that the overall experience so far is limited and without prospective data, the ASTRO consensus statement regarding the patient selection criteria and best practices for the use of APBI outside the context of a clinical trial categorized DCIS as a “Cautionary” group (59). The NSABP B-39/RTOG 0413 phase III clinical trial comparing ABPI versus standard WBI for early-stage breast cancer post excision accrued 4,216 women between 2005 and 2013, and 24.4%, or 1,028, are DCIS. The pending outcome from this trial will clarify which DCIS patients are best suited to APBI post lumpectomy.
Tamoxifen
Tamoxifen use for DCIS developed from its observed benefit in reducing ipsilateral recurrent and new contralateral breast events in the management of invasive breast cancer treated with breast-conserving therapy (60). While radiotherapy post lumpectomy for DCIS results in a relative 50% to 60% reduction in ipsilateral breast recurrence, the residual absolute recurrence rates of between 9% and 20% or higher in some cohorts at 10 to 15 years follow-up (Table 23-2) have left opportunity for improvement. Two clinical trials have tested the impact of tamoxifen after lumpectomy with or without WBI for further reducing breast cancer events for DCIS: NSABP B-24 (2, 61) and UK/ANZ (4, 43). The NSABP B-24 clinical trial tested the hypothesis that in patients with DCIS treatment with lumpectomy, postoperative WBI and tamoxifen would be more effective than lumpectomy with WBI alone in prevention of invasive and non-invasive cancers in the ipsilateral and contralateral breast (61). This double-blind, randomized controlled trial enrolled 1,804 patients between 1991 and 1994 who all received lumpectomy and ipsilateral breast radiotherapy and then were randomly assigned to receive either placebo (n = 902) or tamoxifen (n = 902). Tamoxifen dose was 10 mg twice daily. Thirty-one percent of patients who started therapy discontinued treatment before 5 years. The patient population in this study included 33.5% who were less than 50 years of age, 83% whose DCIS was detected by mammography, 84% that had a lesion size less than 1 cm, and 25% who had positive or unknown surgical margins. At a median follow-up of 6.2 years, there were 37% fewer breast
cancer events in the tamoxifen group than the placebo group (p = .0009). A lower rate of ipsilateral-breast recurrences in the tamoxifen group was apparent only for invasive tumors (44% reduction). The rate of ipsilateral DCIS recurrences was not significantly lower in the tamoxifen group (p = ·43), but the reduction in contralateral breast DCIS was 13 versus 3, a 78% reduction (p = .02). Long-term outcomes of NSABP B-24 reporting at a median follow-up of 13.6 years (2) demonstrate a sustained 32% reduction in the risk of invasive ipsilateral recurrence in the tamoxifen compared with the placebo group (HR, 0.68; 95% CI, 0.49-0.95; p = .025). Regarding ipsilateral DCIS recurrences, the addition of tamoxifen resulted in a non-statistically significant risk reduction of 16% compared with placebo (HR, 0.84; 95% CI, 0.60-1.19; p = .33). There was a 32% reduction in contralateral breast cancer for patients who received tamoxifen versus placebo (HR, 0.68; 95% CI, 0.48-0.95; p = .023).
cancer events in the tamoxifen group than the placebo group (p = .0009). A lower rate of ipsilateral-breast recurrences in the tamoxifen group was apparent only for invasive tumors (44% reduction). The rate of ipsilateral DCIS recurrences was not significantly lower in the tamoxifen group (p = ·43), but the reduction in contralateral breast DCIS was 13 versus 3, a 78% reduction (p = .02). Long-term outcomes of NSABP B-24 reporting at a median follow-up of 13.6 years (2) demonstrate a sustained 32% reduction in the risk of invasive ipsilateral recurrence in the tamoxifen compared with the placebo group (HR, 0.68; 95% CI, 0.49-0.95; p = .025). Regarding ipsilateral DCIS recurrences, the addition of tamoxifen resulted in a non-statistically significant risk reduction of 16% compared with placebo (HR, 0.84; 95% CI, 0.60-1.19; p = .33). There was a 32% reduction in contralateral breast cancer for patients who received tamoxifen versus placebo (HR, 0.68; 95% CI, 0.48-0.95; p = .023).
A combined analysis of outcomes from NSABP B-24 and B-17 that looks across trials demonstrates that radiotherapy and tamoxifen together resulted in a 70% relative risk reduction of invasive ipsilateral breast recurrence compared to lumpectomy alone (2). RT decreased the cumulative incidence of invasive ipsilateral recurrence at 15 years from 19.4% in the lumpectomy-only to 8.9% in the B-17 Lumpectomy-RT group, and to 10% in the B-24 lumpectomy-RT + placebo group. The cumulative incidence of ipsilateral invasive cancer recurrence was lower in the lumpectomy-WBI-tamoxifen group: 8.5% at 15 years.
In NSABP B-24, the addition of tamoxifen did not result in a statistically significant reduction in breast cancer mortality risk (HR, 0.86; 95% CI, 0.66-1.11) compared with lumpectomy and radiotherapy alone. However, across the B-24 and B-17 trials, women who developed an invasive ipsilateral breast recurrence, relative to those who did not, had a greater risk of all-cause death (HR, 1.75; 95% CI, 1.24-2.45), and the effect was larger (HR, 7.06; 95% CI, 4.14-12.03) if only breast cancer-related deaths were considered (2). In contrast, there was no statistically significant increase in overall mortality risk (HR, 0.81; 95% CI, 0.51-1.27) or breast cancer mortality risk (HR, 1.49; 95% CI, 0.71-3.15) for those who had DCIS recurrence. Of note, women who developed an invasive contralateral breast cancer had an increase in mortality risk (HR, 2.62; 95% CI, 1.82-3.77) similar to those who developed an ipsilateral invasive breast cancer recurrence.
The estrogen receptor (ER) status was unknown for the DCIS cases enrolled in NSABP B-24. Retrospectively, ER and/or progesterone receptor (PR) status has been attained in 732 cases, either from tissue blocks (449 patients) or from the laboratories (283 patients) used by enrolling institutions (62). The ER and PR were positive in 76% and 66% of patients, respectively. Patients with ER positive DCIS who received adjuvant tamoxifen versus placebo showed significant reductions in any breast cancer event (HR, 0.58; p = .0015), any invasive breast cancer (HR, 0.53; p = .005), and any contralateral breast cancer (HR, 0.50; p = .02). No significant benefit of tamoxifen in addition to lumpectomy and radiotherapy was seen with ER negative DCIS.
The benefit of tamoxifen after lumpectomy alone or with breast radiotherapy was also evaluated in the UK/ANZ trial in which 1,576 patients were randomly allocated to receive tamoxifen dosed at 20 mg per day (n = 794) or not given tamoxifen (n = 782). Of these, 912 were randomized in a 2 × 2 design to radiotherapy and tamoxifen, while 664 chose no radiotherapy and were only randomized to tamoxifen. Eleven percent stopped taking the drug before 5 years. Sixty-seven percent did not receive breast radiotherapy after lumpectomy (n = 1,053), and 33% underwent WBI post lumpectomy (n = 523). At a median follow-up of 4.4 years, tamoxifen did not significantly reduce the overall event rate nor the ipsilateral breast recurrence rate (13% with tamoxifen versus 15% without, p = .42) (43). In contrast, by median follow-up of 12.7 years, the use of tamoxifen did reduce the overall breast cancer event rate (ipsilateral + contralateral) (18.1% with tamoxifen vs. 24.6% without, p = .002) and the ipsilateral breast cancer event rate (15.7% with tamoxifen and 19.6% without, p = .04) (4). There was a significantly reduced rate of recurrent ipsilateral DCIS (8.6% with tamoxifen vs. 12.1% without, respectively, p = .03), but not ipsilateral invasive disease (6.8% with and 6.9% without tamoxifen, p = .79). Women who were randomly assigned to tamoxifen but were not treated with radiotherapy (n = 1,053) also had a significant overall reduction in new breast events (13.2% with tamoxifen and 17% without, p = .04). However, this benefit was confined to a reduction in DCIS events (7.4% with tamoxifen vs. 10.4% without, p = .04); no difference in invasive recurrences was seen (5.5% with tamoxifen versus 6% without, p = .6). There was no apparent benefit from receipt of tamoxifen among those who had lumpectomy with radiotherapy (n = 532; ipsilateral event rate with tamoxifen 2.4% vs. 2.6% without, p = .8) (4). There was a significant reduction in all contralateral events in those randomly assigned to tamoxifen (1.9% vs. 4.2%, p = .005).
The apparent discordance in the results from NSABP B-24 and UK/ANZ, especially in regard to tamoxifen benefit in the irradiated patients, may reflect the differences in patient populations enrolled in these respective trials. Thirty percent of patients enrolled in NSABP B-24 were less than 50 years of age compared to only 9% in the UK/ANZ trial. This disparity in younger women who have a higher likelihood of in-breast recurrence and proportionally smaller benefit from radiotherapy compared to women older than 50 (44) may explain the greater tamoxifen impact in irradiated patients in the NSABP B-24 trial.
Aromatase Inhibitors and Trastuzumab
The success of tamoxifen in lowering all rates of recurrence encourages the search for more effective and/or less toxic agents to reduce recurrent and new breast cancer events following lumpectomy for DCIS. Aromatase inhibitors have been documented to prevent invasive breast cancer in postmenopausal women (63) and reduce new contralateral breast cancer to a greater extent than tamoxifen after treatment of endocrine-sensitive invasive breast cancer (64). The outcomes from two randomized clinical trials that have completed accrual and that test the relative benefit of anastrozole in comparison to tamoxifen for reducing breast cancer events after lumpectomy for DCIS are awaited. Between 2003 and 2007, NSABP B-35 randomized 3,000 postmenopausal women diagnosed with DCIS treated with lumpectomy and breast radiotherapy in double-blind fashion to 5 years of tamoxifen 20 mg daily (and an anastrozole appearing placebo) versus anastrozole 1mg daily (and a tamoxifen appearing placebo). The International Breast Cancer Intervention Study II (IBIS II) similarly randomized 2,980 women over age 40 who had undergone lumpectomy for DCIS to either 5 years of tamoxifen or anastrozole between 2003 and 2011.
Trastuzumab has been demonstrated to be effective and safe in the treatment of HER2 overexpressing invasive breast cancer. HER2 overexpression in DCIS can range from 30% to 50% (65) and has been associated with higher rates of subsequent ipsilateral breast cancer recurrence (66). NSABP B-43 is actively accruing women with HER2 overexpressing DCIS treated with lumpectomy to be randomized to standard WBI versus 2 doses of trastuzumab every 3 weeks during
radiotherapy to determine whether trastuzumab given concurrently with radiotherapy is beneficial in preventing subsequent breast cancer events. The targeted accrual is 2,000, and as of the close of 2012, over 1,000 patients have been randomized.
radiotherapy to determine whether trastuzumab given concurrently with radiotherapy is beneficial in preventing subsequent breast cancer events. The targeted accrual is 2,000, and as of the close of 2012, over 1,000 patients have been randomized.
Breast-Conserving Surgery Alone
The four published prospective, randomized trials (2, 3, 4 and 5) have demonstrated that the addition of RT to excision significantly decreases ipsilateral breast tumor recurrence (IBTR) but does not improve overall or disease-specific survival. It is possible that with larger populations and follow-up that some difference would emerge, but with randomization of approximately 4,000 women and median follow-up of 8 to 17 years, no hint of such a trend exists. Because radiation has not improved survival, and because there are rare but potentially serious risks associated with radiation, including secondary malignancies and cardiac disease (47, 67), there has been persistent interest in treating some subsets of women with DCIS by excision alone. In fact, most academic radiation oncologists surveyed would not recommend radiation to all women with DCIS (68). Numerous risk factors for local recurrence have been identified, leading to the belief that at least some subset of DCIS may have a recurrence risk low enough to not justify radiation. A number of retrospective studies, usually including a highly select group of patients with small mammographically detected tumors of low histologic grade, have suggested that DCIS can be treated with excision alone with a high rate of local control. A number of these studies are shown in Table 23-6.
There have been two prospective studies of wide excision alone for DCIS (Table 23-7). The Dana-Farber/Harvard Cancer Center conducted a single-arm, prospective trial of wide excision alone from 1995 to 2002 (80, 136). Entry criteria included DCIS of predominant grade 1 or 2 with a mammographic extent of no greater than 2.5 cm and final margin width of at least 1 cm. Tamoxifen was not permitted. The accrual goal was 200 patients; in July 2002 the study closed to further accrual at 158 patients because the number of local recurrences (n = 13) met the stopping rules. The median patient age was 51 years, and 94% had mammographically detected DCIS. Re-excision was performed in 133 (84%) of which no residual disease was identified in 92%. The median follow-up was 3.6 years (range, 0 to 6.9 years). Thirteen patients had local recurrence as the first site of failure between 0.6 and 5.2 years, resulting in a rate of ipsilateral local recurrence of 2.4% per patient-year (95% CI, 1.3%—4.1%), corresponding to a 5-year rate of 12%. Ten recurrences were in the same quadrant as the initial DCIS and three were elsewhere in the ipsilateral breast. Four (31%) recurred with invasive disease, all under 1 cm in size, and none with nodal metastases. No patient developed distant metastasis. A recent update with median follow-up of 11 years reported an annual local recurrence rate of 1.9% per patient-year and a 10-year local recurrence rate of 15.6% (136).
TABLE 23-6 Results of Treatment of Ductal Carcinoma In Situ with Excision Alone, Retrospective Series | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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