sabato 6 febbraio 2010
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The risk of breast cancer increases exponentially up to the age of menopause, at which time the rate of increase in the risk slows significantly. After the age of 80, the incidence of breast cancer begins to show a slight decline. For women in their late 30s, the annual increase in risk of developing breast cancer is approximately 0.07% per year. This increases to 0.44% per year for women in their late 70s. Although these percentages may seem low, they represent only the risk for a given year; the lifetime risk is a summation of the annual breast cancer risks. Because younger women have a longer life expectancy than older women, younger women have a greater lifetime risk. Only 0.43% of women develop breast cancer before the age of 40, whereas 4% of women develop breast cancer between the ages of 40 and 59 and 6.88% of women develop breast cancer between the ages of 60 and 79 (379).
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Table 53.1 summarizes the major risk factors associated with development of breast cancer. With the exception of female gender, increasing age is the most consistent and significant risk factor, with most populations demonstrating increasing incidence rates with age. Other risk factors include personal history and family history of breast cancer, nulliparity or late age at first childbirth, early menarche and late menopause, prior breast biopsy with hyperplasia or atypical hyperplasia, high breast tissue density, radiation exposure at a young age, alcohol consumption, and use of postmenopausal hormone therapy. Some of the national origin/ethnicity variability discussed above may be explained in part by differences in established risk factors, such as age of menarche, parity, and age at first childbirth. However, these factors explain only in part the variability observed in national origin, indicating that underlying genetic, environmental, and dietary factors are likely to contribute to the differences in the worldwide incidence of breast cancer (127). Breastfeeding, physical activity, and maintaining a healthy body weight have been demonstrated in various studies to be associated with a lower risk of breast cancer (127).
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Breast cancer is the most frequently diagnosed cancer in women, and it is estimated that there will be 212,920 new cases of invasive breast cancer and 61,980 new cases of in situ breast cancers among women in the United States in 2006 (16,379). Primarily due to increased utilization of screening mammography, breast cancer incidence rates increased rapidly in the 1980s. It is estimated that 41,430 breast cancer deaths will occur in 2006, with breast cancer ranking second among cancer deaths in women (after lung cancer). In contrast to the significant number of breast cancer cases in women, it is expected that 1,720 cases of breast cancer will be diagnosed in men in 2006, with approximately 460 breast cancer deaths in men. Due to a combination of early detection, increased awareness, and improvements in therapy, death rates from breast cancer actually declined by approximately 2.3% per year from 1990 to 2002 (379). The decrease in breast cancer mortality is demonstrated in Fig. 53.5.
There is considerable geographic, ethnic, and racial variability in breast cancer incidence. Ethnicity and national origin rank highly as predictors of risk for breast cancer with up to a 10-fold variation throughout the world (461). Compared to other well-established risk factors such as age of menarche and menopause, age at first childbirth, and family history, geographic and ethnic variability is quite significant. It is likely that a complex interaction of multiple factors, including genetic, environmental, and socioeconomic, contribute to the wide variability in age-adjusted incidence across populations.
The potential contribution of environmental factors and lifestyle is clearly demonstrated in the increasing incidence of breast cancers among Japanese American women and in trends of increasing incidence of breast cancer in Japan with recent changes in lifestyle. It is well recognized that the relatively low incidence of breast cancer in Asian immigrants to the United States has gradually increased as these immigrants have adapted to Western lifestyles (150). Rates of breast cancer over time in Japanese women in Los Angeles are now approaching the incidence in Caucasian women. In Japan, incidence rates have more than doubled from 1960 to 1990. This is likely a result of adaptation of Western lifestyles including fewer children, later marriage, increasing rates of obesity, and possibly dietary influences (112).
In the United States, the incidence of breast cancer in white women is higher than all other populations. Recent data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program report incidence rates of 141 cases per 100,000 white women, compared to 122 in African American, 97 in Asian Pacific Islander, 90 in Hispanics, and 58 in American/Alaskan Natives (379).
Although incidence is lower in African American women, the age of onset is younger and African American women are more likely to be diagnosed at a more advanced stage. Several studies have reported an earlier onset of breast cancer in African American compared to white women by approximately 10 years. Furthermore, several studies have reported, after correcting for stage, that African American women have more aggressive biology and a poorer overall prognosis (62,385).
There is considerable geographic, ethnic, and racial variability in breast cancer incidence. Ethnicity and national origin rank highly as predictors of risk for breast cancer with up to a 10-fold variation throughout the world (461). Compared to other well-established risk factors such as age of menarche and menopause, age at first childbirth, and family history, geographic and ethnic variability is quite significant. It is likely that a complex interaction of multiple factors, including genetic, environmental, and socioeconomic, contribute to the wide variability in age-adjusted incidence across populations.
The potential contribution of environmental factors and lifestyle is clearly demonstrated in the increasing incidence of breast cancers among Japanese American women and in trends of increasing incidence of breast cancer in Japan with recent changes in lifestyle. It is well recognized that the relatively low incidence of breast cancer in Asian immigrants to the United States has gradually increased as these immigrants have adapted to Western lifestyles (150). Rates of breast cancer over time in Japanese women in Los Angeles are now approaching the incidence in Caucasian women. In Japan, incidence rates have more than doubled from 1960 to 1990. This is likely a result of adaptation of Western lifestyles including fewer children, later marriage, increasing rates of obesity, and possibly dietary influences (112).
In the United States, the incidence of breast cancer in white women is higher than all other populations. Recent data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program report incidence rates of 141 cases per 100,000 white women, compared to 122 in African American, 97 in Asian Pacific Islander, 90 in Hispanics, and 58 in American/Alaskan Natives (379).
Although incidence is lower in African American women, the age of onset is younger and African American women are more likely to be diagnosed at a more advanced stage. Several studies have reported an earlier onset of breast cancer in African American compared to white women by approximately 10 years. Furthermore, several studies have reported, after correcting for stage, that African American women have more aggressive biology and a poorer overall prognosis (62,385).
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The level I axilla is caudal and lateral to the muscle, level II is beneath the muscle, and level III (also known as the infraclavicular region) is cranial and medial to the muscle. A standard axillary lymph node dissection resects the tissue and lymph nodes within levels I and II. It is very unusual to have involvement of level III of the axilla without disease in level I or II. The axillary lymph nodes continue underneath the clavicle to become the supraclavicular lymph nodes, which can be involved in locally advanced breast cancers.
Lymphatics can also drain directly into the internal mammary lymph node chain (IMC), which are intrathoracic structures located in the parasternal space. Although these nodes are not usually visualized on computed tomography (CT), the anatomical region of the IMC can be determined by the internal mammary artery and vein, which are easily visualized by CT (Fig. 53.3), and usually lie 3 to 4 cm lateral to midline. When breast cancer involves the IMC, the majority of cases will have disease that is limited to lymph nodes in the first three interspaces. Regardless of the location within the breast, the axilla is the most common site of lymphatic involvement. However, breast cancers that develop in the medial, central, or lower breast more commonly drain to the IMC (in addition to the axilla) than those occurring in the lateral and upper quadrants.
The use of lymphoscintigraphy, by injecting technetium-99 radiocolloid into the peritumoral region, followed by scintillation scanning, is used now for sentinel lymph node imaging. This technique has helped to delineate primary lymphatic drainage patterns of breast cancer. In a study reported by Estourgie et al. (190) of 700 patients undergoing sentinel node mapping, the distribution of axillary and internal mammary drainage is summarized in Fig. 53.4. Even in inner-quadrant lesions, axillary drainage is more common than internal mammary drainage. However, internal mammary drainage was present in over 50% of lower inner-quadrant lesions.
Lymphatics can also drain directly into the internal mammary lymph node chain (IMC), which are intrathoracic structures located in the parasternal space. Although these nodes are not usually visualized on computed tomography (CT), the anatomical region of the IMC can be determined by the internal mammary artery and vein, which are easily visualized by CT (Fig. 53.3), and usually lie 3 to 4 cm lateral to midline. When breast cancer involves the IMC, the majority of cases will have disease that is limited to lymph nodes in the first three interspaces. Regardless of the location within the breast, the axilla is the most common site of lymphatic involvement. However, breast cancers that develop in the medial, central, or lower breast more commonly drain to the IMC (in addition to the axilla) than those occurring in the lateral and upper quadrants.
The use of lymphoscintigraphy, by injecting technetium-99 radiocolloid into the peritumoral region, followed by scintillation scanning, is used now for sentinel lymph node imaging. This technique has helped to delineate primary lymphatic drainage patterns of breast cancer. In a study reported by Estourgie et al. (190) of 700 patients undergoing sentinel node mapping, the distribution of axillary and internal mammary drainage is summarized in Fig. 53.4. Even in inner-quadrant lesions, axillary drainage is more common than internal mammary drainage. However, internal mammary drainage was present in over 50% of lower inner-quadrant lesions.
venerdì 5 febbraio 2010
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The management of DCIS requires the coordinated, multidisciplinary interaction of radiologists, surgeons, pathologists, and oncologists. Patients are first assessed to determine if they are candidates for breast-conserving surgery. Women with multicentric DCIS, as defined by the presence of two or more tumors in separate quadrants of the breast, and those with extensive or diffuse DCIS or suspicious-appearing microcalcifications throughout the breast are candidates for mastectomy, as are women in whom negative margins or acceptable cosmesis cannot be achieved with the use of breast-conserving surgery. Some women may prefer mastectomy to breast conservation in order to minimize the chance of ipsilateral recurrence or for other reasons. At present, there is no established role for the use of magnetic resonance imaging in screening patients for DCIS in determining whether breast-conserving surgery is an option.
Patients deemed to be appropriate candidates for breast conservation require complete surgical excision of the affected area. The extent of DCIS in the breast and the existing margin determine the likelihood of identifying residual disease on reexcision. Nearly half of patients with margins that are <1 mm have residual DCIS on re-excision (82). However, the optimal margin width for the management of DCIS is not known. At a minimum, there should be no tumor at the margin.
Neither dissection of axillary lymph nodes nor mapping of sentinel lymph nodes is routinely warranted in patients with DCIS because of the very low incidence of axillary metastases (110). Three to 13% of patients with DCIS, and a slightly greater percentage with DCIS and microinvasion, have isolated tumor cells in sentinel axillary lymph nodes (62). The prognostic significance of these cells is not clear. Clinical experience suggests that patients have a much better outcome than would be predicted by such rates of nodal metastases, and most instances represent micrometastases of unclear metastatic potential. However, sentinel lymph node mapping may be used in selected patients with a higher likelihood of occult invasive cancer—those with extensive, high-grade DCIS or palpable masses—and those undergoing mastectomy as sentinel node mapping cannot be performed afterward if invasive tumor is identified (79).
After breast-conserving surgery, radiotherapy is administered using tangential fields to the whole breast with a standard dose of 45 to 50 Gy delivered in daily fractions of 180 to 200 cGy. On the basis of extrapolation from data on the treatment of invasive breast cancer (11), a radiation boost to the tumor bed may be added to whole-breast treatment, particularly for women with close surgical margins, although the benefit of a boost in the management of DCIS is not established. There is no role for postmastectomy or nodal irradiation in the treatment of DCIS.
It is not yet possible to prospectively identify women who are at sufficiently low risk that radiotherapy may not be of some clinical advantage in preventing recurrences. After discussing the various options, patients may elect not to receive radiation treatment, but they must understand and accept the increased risk of recurrence that this choice probably entails.
In summary, despite considerable advances in our clinical knowledge base, the answer to the question “when should radiotherapy be used for DCIS?” remains complex and surrounded by considerable controversy. Two fundamental considerations must be emphasized:
• A primary goal of breast-conserving therapy for DCIS is to achieve the best possible cosmetic outcome. Attempts to obtain wide surgical margins through deforming, large-volume breast excisions represent cosmetic failures and defeat the purpose of breast conservation.
• Breast irradiation reduces the risk of subsequent invasive or noninvasive carcinoma in the treated breast and thus reduces the risk of the ultimate cosmetic failure— mastectomy.
According to prospectively randomized trials of breast-conserving therapy for DCIS, radiotherapy reduces subsequent breast recurrence in all patient groups irrespective of prognostic risk factors. That is not to say, however, that radiotherapy must be used for all patients with DCIS. In all cases, a realistic and balanced discussion of the relative risks and benefits of treatment options should be presented to the patient. Reasonable estimates of breast recurrence during the ensuing decade with or without radiotherapy are available based on level I evidence from prospective clinical trials. A decision tree to assist in the selection of treatment options is presented in Table 52.5.
Patients deemed to be appropriate candidates for breast conservation require complete surgical excision of the affected area. The extent of DCIS in the breast and the existing margin determine the likelihood of identifying residual disease on reexcision. Nearly half of patients with margins that are <1 mm have residual DCIS on re-excision (82). However, the optimal margin width for the management of DCIS is not known. At a minimum, there should be no tumor at the margin.
Neither dissection of axillary lymph nodes nor mapping of sentinel lymph nodes is routinely warranted in patients with DCIS because of the very low incidence of axillary metastases (110). Three to 13% of patients with DCIS, and a slightly greater percentage with DCIS and microinvasion, have isolated tumor cells in sentinel axillary lymph nodes (62). The prognostic significance of these cells is not clear. Clinical experience suggests that patients have a much better outcome than would be predicted by such rates of nodal metastases, and most instances represent micrometastases of unclear metastatic potential. However, sentinel lymph node mapping may be used in selected patients with a higher likelihood of occult invasive cancer—those with extensive, high-grade DCIS or palpable masses—and those undergoing mastectomy as sentinel node mapping cannot be performed afterward if invasive tumor is identified (79).
After breast-conserving surgery, radiotherapy is administered using tangential fields to the whole breast with a standard dose of 45 to 50 Gy delivered in daily fractions of 180 to 200 cGy. On the basis of extrapolation from data on the treatment of invasive breast cancer (11), a radiation boost to the tumor bed may be added to whole-breast treatment, particularly for women with close surgical margins, although the benefit of a boost in the management of DCIS is not established. There is no role for postmastectomy or nodal irradiation in the treatment of DCIS.
It is not yet possible to prospectively identify women who are at sufficiently low risk that radiotherapy may not be of some clinical advantage in preventing recurrences. After discussing the various options, patients may elect not to receive radiation treatment, but they must understand and accept the increased risk of recurrence that this choice probably entails.
In summary, despite considerable advances in our clinical knowledge base, the answer to the question “when should radiotherapy be used for DCIS?” remains complex and surrounded by considerable controversy. Two fundamental considerations must be emphasized:
• A primary goal of breast-conserving therapy for DCIS is to achieve the best possible cosmetic outcome. Attempts to obtain wide surgical margins through deforming, large-volume breast excisions represent cosmetic failures and defeat the purpose of breast conservation.
• Breast irradiation reduces the risk of subsequent invasive or noninvasive carcinoma in the treated breast and thus reduces the risk of the ultimate cosmetic failure— mastectomy.
According to prospectively randomized trials of breast-conserving therapy for DCIS, radiotherapy reduces subsequent breast recurrence in all patient groups irrespective of prognostic risk factors. That is not to say, however, that radiotherapy must be used for all patients with DCIS. In all cases, a realistic and balanced discussion of the relative risks and benefits of treatment options should be presented to the patient. Reasonable estimates of breast recurrence during the ensuing decade with or without radiotherapy are available based on level I evidence from prospective clinical trials. A decision tree to assist in the selection of treatment options is presented in Table 52.5.
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The NSABP B-24 trial (42) compared excision plus radiotherapy to excision, radiotherapy, and tamoxifen. Patients who received tamoxifen had a decreased incidence of breast cancer events (invasive or noninvasive ipsilateral or contralateral breast cancer) compared with patients who did not receive tamoxifen (8.2% vs. 13.4% at 5 years, respectively; p = .0009), but no survival benefit was found. Tamoxifen therapy resulted in a 44% reduction in the risk of subsequent invasive tumor recurrence but had no significant effect on ipsilateral noninvasive breast recurrence (Table 52.4). Positive tumor margins were significantly associated with breast recurrence, and tamoxifen reduced ipsilateral breast failure by 22% with negative margins and 44% in cases with positive or unknown margins.
In contrast to the findings of the NSABP B-24 trial, the UKCCCR trial found that tamoxifen had no effect in reducing local recurrence rate when combined with whole-breast radiation therapy (Table 52.4). When used as single agent without radiation therapy after lumpectomy, tamoxifen had no effect on the incidence of invasive recurrence but did show a statistically significant reduction in the risk of DCIS recurrence (10% vs. 6%; p = .03) (59). As such, the role of tamoxifen for DCIS in the absence of whole-breast radiotherapy remains to be defined.
Because DCIS is a precursor to invasive breast cancer and shares many biologic features of invasive carcinoma, it is increasingly recognized as a target for preventive measures. In the largest trials of the prevention of primary breast cancer among women at high risk for breast cancer by virtue of age, family history, or prior benign breast disease, tamoxifen reduced the risk of DCIS by 50% to 70% (27,40).
In contrast to the findings of the NSABP B-24 trial, the UKCCCR trial found that tamoxifen had no effect in reducing local recurrence rate when combined with whole-breast radiation therapy (Table 52.4). When used as single agent without radiation therapy after lumpectomy, tamoxifen had no effect on the incidence of invasive recurrence but did show a statistically significant reduction in the risk of DCIS recurrence (10% vs. 6%; p = .03) (59). As such, the role of tamoxifen for DCIS in the absence of whole-breast radiotherapy remains to be defined.
Because DCIS is a precursor to invasive breast cancer and shares many biologic features of invasive carcinoma, it is increasingly recognized as a target for preventive measures. In the largest trials of the prevention of primary breast cancer among women at high risk for breast cancer by virtue of age, family history, or prior benign breast disease, tamoxifen reduced the risk of DCIS by 50% to 70% (27,40).
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Ipsilateral tumor recurrences in patients with DCIS are usually detected on surveillance mammography, although one-quarter may be detected on the basis of changes on physical examination of the breast or chest wall (75,118). For this reason, patients should be scheduled for a baseline mammogram 6 to 12 months after initial therapy and at least annually thereafter. Distant breast cancer metastases in the absence of regional recurrence are unusual. Local recurrences after breast-conserving surgery and radiotherapy are generally treated with mastectomy. Selected patients with local recurrences who have not previously received radiotherapy may be candidates for local excision and radiotherapy. The clinical outcome of ipsilateral tumor recurrence is governed by the nature of the recurrence. Patients with recurrent DCIS have an excellent prognosis, with less than a 1% risk of further recurrence after salvage mastectomy. Patients with invasive recurrence after breast-conserving surgery for DCIS have a prognosis similar to those with early-stage breast cancer, with a 15% to 20% risk of metastatic recurrence at 8 years (118).
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Patient age is an important prognostic variable for local recurrence after breast conservation for DCIS (15,42,117,127). In younger patients, DCIS more frequently contains adverse prognostic pathologic features and extends over a greater distance in the breast than in older patients (127). In series with adequate follow-up, younger patients treated with lumpectomy and radiation therapy had a significantly higher rate of local recurrence than older patients, especially for invasive local recurrences (127). Some studies have suggested that careful attention to margin status and excising larger volumes of tissue can reduce this difference substantially (117,127). No available data show that younger patients have better long-term cancer-free survival rates if treated by mastectomy rather than lumpectomy and radiation therapy. Successful treatment of younger patients with DCIS with lumpectomy and radiation therapy requires careful attention to patient evaluation, selection, and surgical technique. When this is done, age at diagnosis should not be a contraindication to breast-conserving therapy.
A number of recent studies have attempted to identify and treat patients with highly selected favorable tumor characteristics with excision alone (i.e., without whole-breast irradiation) and report 10-year local failure rates of 3% to 25% (109,111). A scoring system has been proposed (108) using histopathologic features including tumor size, grade, and margin width in an attempt to stratify patients according to local failure risk after excision plus or minus whole-breast irradiation. Each variable was assigned a score of 1 to 3, and the sum total defined the Van Nuys Prognostic Index. Although appealingly simple, this scheme (108) is drawn from the retrospective analysis of a patient cohort in which there exist a number of methodologic shortcomings and it has not been independently validated (29).
Wong et al. (134) performed a prospective study that attempted to identify patients with “low-risk” DCIS who can be spared whole-breast radiation therapy. This trial enrolled 158 patients with lesions that were mostly grade 1 or 2 and with a mammographic extent of ≤2.5 cm who were treated with wide excision, with final margins of ≥1 cm or a re-excision without residual DCIS. Tamoxifen was not permitted. The median age was 51 years and the median follow-up was 40 months. The rate of ipsilateral local recurrence was 2.4% per patient-year, corresponding to a 5-year rate of 12%. Nine patients (69%) experienced recurrence of DCIS and four (31%) experienced recurrence with invasive carcinoma. These data provide prospective evidence that, despite margins of >1 cm, the local recurrence rate is substantial even in patients with small, grade 1 or 2 DCIS following treatment with wide excision alone.
Presently, the Radiation Therapy Oncology Group is conducting a prospective randomized trial to further assess the need for radiotherapy in low-risk DCIS. Following lumpectomy with ≥3 mm clear margins of resection, patients are stratified according to age (<50 vs. ≥50 years), tumor size (≤1 vs. >1 to 2.5 cm), margin status (negative re-excision vs. 3 to 9 vs. ≥10 mm), grade, and the use of tamoxifen (at the discretion of the managing physician). Following stratification, patients are randomized to whole-breast irradiation versus observation. The NSABP and Radiation Therapy Oncology Group have jointly launched a phase III accelerated partial-breast irradiation trial that randomly allocates patients between standard whole-breast irradiation following lumpectomy versus accelerated partial-breast irradiation to determine if in-breast control rates are comparable. As the in-breast failure patterns for DCIS suggest that treatment directed to the primary lesion plus a 2-cm margin should achieve local control rates that equate to whole-breast treatment approaches, patients with pure DCIS or DCIS and LCIS will be eligible for stratified randomization.
A number of recent studies have attempted to identify and treat patients with highly selected favorable tumor characteristics with excision alone (i.e., without whole-breast irradiation) and report 10-year local failure rates of 3% to 25% (109,111). A scoring system has been proposed (108) using histopathologic features including tumor size, grade, and margin width in an attempt to stratify patients according to local failure risk after excision plus or minus whole-breast irradiation. Each variable was assigned a score of 1 to 3, and the sum total defined the Van Nuys Prognostic Index. Although appealingly simple, this scheme (108) is drawn from the retrospective analysis of a patient cohort in which there exist a number of methodologic shortcomings and it has not been independently validated (29).
Wong et al. (134) performed a prospective study that attempted to identify patients with “low-risk” DCIS who can be spared whole-breast radiation therapy. This trial enrolled 158 patients with lesions that were mostly grade 1 or 2 and with a mammographic extent of ≤2.5 cm who were treated with wide excision, with final margins of ≥1 cm or a re-excision without residual DCIS. Tamoxifen was not permitted. The median age was 51 years and the median follow-up was 40 months. The rate of ipsilateral local recurrence was 2.4% per patient-year, corresponding to a 5-year rate of 12%. Nine patients (69%) experienced recurrence of DCIS and four (31%) experienced recurrence with invasive carcinoma. These data provide prospective evidence that, despite margins of >1 cm, the local recurrence rate is substantial even in patients with small, grade 1 or 2 DCIS following treatment with wide excision alone.
Presently, the Radiation Therapy Oncology Group is conducting a prospective randomized trial to further assess the need for radiotherapy in low-risk DCIS. Following lumpectomy with ≥3 mm clear margins of resection, patients are stratified according to age (<50 vs. ≥50 years), tumor size (≤1 vs. >1 to 2.5 cm), margin status (negative re-excision vs. 3 to 9 vs. ≥10 mm), grade, and the use of tamoxifen (at the discretion of the managing physician). Following stratification, patients are randomized to whole-breast irradiation versus observation. The NSABP and Radiation Therapy Oncology Group have jointly launched a phase III accelerated partial-breast irradiation trial that randomly allocates patients between standard whole-breast irradiation following lumpectomy versus accelerated partial-breast irradiation to determine if in-breast control rates are comparable. As the in-breast failure patterns for DCIS suggest that treatment directed to the primary lesion plus a 2-cm margin should achieve local control rates that equate to whole-breast treatment approaches, patients with pure DCIS or DCIS and LCIS will be eligible for stratified randomization.
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Three prospective randomized studies of excision only versus excision plus breast irradiation for DCIS have been performed, and all have shown that the rate of local recurrence was reduced with the addition of radiation (Table 52.1). The NSABP B-17 trial (41,43) consisted of 818 patients who were stratified by age (49 years of age or younger vs. older than 49 years), DCIS versus DCIS plus LCIS, method of detection, and whether an axillary dissection was performed. Tumor size was determined by mammogram, gross pathologic measurement, or clinical examination. Of the patients enrolled, 83% had nonpalpable tumors. The 12-year rate of local recurrence was 15.7% with radiation and 31.7% without radiation (p <.000005) (Fig. 52.6). The average annual incidence rates of all ipsilateral breast tumor recurrences, ipsilateral noninvasive recurrences, and ipsilateral invasive recurrences were reduced with breast irradiation by 59%, 47%, and 71%, respectively. An analysis of clinical variables showed that microcalcifications extending beyond a maximum dimension of >1 cm were associated with an elevated risk of breast recurrence. A central pathology review was performed, including a multivariate analysis of histopathologic variables (Table 52.2), that revealed only moderate/marked comedonecrosis as being significantly associated with local failure risk. Margin status (free vs. unknown/involved) was of borderline significance.
The EORTC 10853 trial (14,67) randomly allocated 1,010 patients with 5 cm or smaller DCIS and negative margins to excision versus excision plus breast irradiation. Lesions were nonpalpable in 79% of patients, and the mean maximal tumor diameter was approximately 2 cm. The 10-year rate of local recurrence was 15% for patients treated with radiation, as compared with 25% for patients treated without radiation (p <.0001). At a median follow-up of 10.2 years, radiation therapy resulted in risk reduction for both invasive and noninvasive breast relapse of 42%. As with the NSABP B-17 study, a central pathology review was performed (14,15). In a multivariate analysis (Table 52.3), factors associated with an increased risk of local recurrence were age 40 years or younger, clinically symptomatic presentation (nipple discharge or palpable mass), intermediate or poorly differentiated DCIS, solid and cribriform histologic growth pattern, involved or uncertain margins, and treatment by local excision alone. The risk of invasive recurrence was not related to histologic type of DCIS, but the risk of distant metastasis was significantly higher in poorly differentiated DCIS compared with well-differentiated DCIS.
The EORTC 10853 trial did not allow the identification of an appropriate margin width for treatment with or without radiotherapy because the eligibility criteria did not require reporting of the margin status. Nonetheless, the central review of cases did provide some information regarding the relative importance of surgical margin as related to local failure risk. A recurrence rate of 24% at 4 years was observed in cases with close/involved margins after excision alone. Radiotherapy was not adequate to compensate for involved margins because even with the application of irradiation the recurrence rate was 20% in this group. These data and others (108,109,116,117) are strongly suggestive that obtaining a microscopic complete excision is essential for optimal local control in breast-conserving therapy for DCIS. Of further note, even in the group of DCIS cases for which margins could be considered optimal (i.e., those patients who underwent a surgical re-excision in which no residual DCIS was found), a 4-year local recurrence rate of 18% was observed when these patients were treated with surgery alone (15).
The UKCCCR DCIS Working group has also conducted a randomized trial investigating the role of adjuvant radiotherapy (59). With a 2 × 2 factorial protocol design, the aim of this study was to compare excision alone versus excision plus tamoxifen versus excision plus radiotherapy versus excision plus radiotherapy and tamoxifen. Tamoxifen was prescribed as 20 mg per day and radiotherapy was delivered through whole-breast tangential fields to a total dose of 50 Gy. Boost was not recommended. A total of 1,030 patients were enrolled. When reported with 4.38 year follow-up, the crude incidence of local recurrence was 14% of the patients who were treated with excision only and 6% when the excision was followed by radiotherapy. The addition of tamoxifen offered no benefit toward overall ipsilateral local control when administered in addition to radiotherapy; however, tamoxifen did appear to reduce the ipsilateral recurrence rate of DCIS (but not invasive carcinoma) in the absence of radiotherapy (59).
Subgroup analyses from randomized trials have demonstrated that the absolute benefits of radiotherapy are greater in women at increased risk for tumor recurrence, such as women with involved surgical margins (identified on retrospective pathologic review), younger women, and those with tumors that have high-grade or comedonecrotic features (14,15,41,43). However, radiotherapy lowers the incidence of recurrence among all subgroups, regardless of the baseline risk.
The EORTC 10853 trial (14,67) randomly allocated 1,010 patients with 5 cm or smaller DCIS and negative margins to excision versus excision plus breast irradiation. Lesions were nonpalpable in 79% of patients, and the mean maximal tumor diameter was approximately 2 cm. The 10-year rate of local recurrence was 15% for patients treated with radiation, as compared with 25% for patients treated without radiation (p <.0001). At a median follow-up of 10.2 years, radiation therapy resulted in risk reduction for both invasive and noninvasive breast relapse of 42%. As with the NSABP B-17 study, a central pathology review was performed (14,15). In a multivariate analysis (Table 52.3), factors associated with an increased risk of local recurrence were age 40 years or younger, clinically symptomatic presentation (nipple discharge or palpable mass), intermediate or poorly differentiated DCIS, solid and cribriform histologic growth pattern, involved or uncertain margins, and treatment by local excision alone. The risk of invasive recurrence was not related to histologic type of DCIS, but the risk of distant metastasis was significantly higher in poorly differentiated DCIS compared with well-differentiated DCIS.
The EORTC 10853 trial did not allow the identification of an appropriate margin width for treatment with or without radiotherapy because the eligibility criteria did not require reporting of the margin status. Nonetheless, the central review of cases did provide some information regarding the relative importance of surgical margin as related to local failure risk. A recurrence rate of 24% at 4 years was observed in cases with close/involved margins after excision alone. Radiotherapy was not adequate to compensate for involved margins because even with the application of irradiation the recurrence rate was 20% in this group. These data and others (108,109,116,117) are strongly suggestive that obtaining a microscopic complete excision is essential for optimal local control in breast-conserving therapy for DCIS. Of further note, even in the group of DCIS cases for which margins could be considered optimal (i.e., those patients who underwent a surgical re-excision in which no residual DCIS was found), a 4-year local recurrence rate of 18% was observed when these patients were treated with surgery alone (15).
The UKCCCR DCIS Working group has also conducted a randomized trial investigating the role of adjuvant radiotherapy (59). With a 2 × 2 factorial protocol design, the aim of this study was to compare excision alone versus excision plus tamoxifen versus excision plus radiotherapy versus excision plus radiotherapy and tamoxifen. Tamoxifen was prescribed as 20 mg per day and radiotherapy was delivered through whole-breast tangential fields to a total dose of 50 Gy. Boost was not recommended. A total of 1,030 patients were enrolled. When reported with 4.38 year follow-up, the crude incidence of local recurrence was 14% of the patients who were treated with excision only and 6% when the excision was followed by radiotherapy. The addition of tamoxifen offered no benefit toward overall ipsilateral local control when administered in addition to radiotherapy; however, tamoxifen did appear to reduce the ipsilateral recurrence rate of DCIS (but not invasive carcinoma) in the absence of radiotherapy (59).
Subgroup analyses from randomized trials have demonstrated that the absolute benefits of radiotherapy are greater in women at increased risk for tumor recurrence, such as women with involved surgical margins (identified on retrospective pathologic review), younger women, and those with tumors that have high-grade or comedonecrotic features (14,15,41,43). However, radiotherapy lowers the incidence of recurrence among all subgroups, regardless of the baseline risk.
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Mastectomy was the standard treatment of DCIS through the first four decades of its recognition as a distinct histopathologic entity. Mastectomy is a highly effective treatment for DCIS, with a locoregional control rate of 96% to 100% and cancer-specific mortality rates of 4% or less (111). No randomized study has compared mastectomy with breast-conservation treatment for DCIS. Therefore, the relative outcomes for mastectomy and breast-conservation treatment can be estimated only by reviewing nonrandomized, retrospective studies. Local treatment failure after mastectomy (111) may occur because of unrecognized invasive carcinoma that results in local recurrence or distant metastasis, or it may be the result of incomplete removal of breast tissue with the subsequent formation of a new primary tumor.
Data from some surgical trials (45) and large treatment registries (35) suggest that the rates of local or regional recurrence are significantly lower after mastectomy than after breast-conserving surgery, but there have been no significant differences in overall survival. Metastatic breast cancer can follow the recurrence of an invasive tumor or the development of cancer in the contralateral breast. However, death related to breast cancer within 10 years after the diagnosis of DCIS occurs in only 1% to 2% of all patients, irrespective of whether mastectomy or breast-conserving surgery was performed (35).
Data from some surgical trials (45) and large treatment registries (35) suggest that the rates of local or regional recurrence are significantly lower after mastectomy than after breast-conserving surgery, but there have been no significant differences in overall survival. Metastatic breast cancer can follow the recurrence of an invasive tumor or the development of cancer in the contralateral breast. However, death related to breast cancer within 10 years after the diagnosis of DCIS occurs in only 1% to 2% of all patients, irrespective of whether mastectomy or breast-conserving surgery was performed (35).
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The goal of treatment with DCIS is prevention of local recurrence, with particular emphasis on the prevention of invasive breast cancer. Treatment decisions are largely based on information provided by mammography and, most especially, pathologic evaluation of the biopsy specimen. As such, in the consideration of treatment options it is important for the clinician to be aware of some of the technical limitations associated with the clinical and histopathologic assessment of DCIS.
Studies performed during the past two decades clearly have suggested that DCIS is not a single disease. Rather, this term encompasses a diverse group of lesions that differ with regard to their clinical presentation, mammographic features, extent and distribution within the breast, histologic characteristics, and biologic markers. Moreover, clinical follow-up studies have indicated that these lesions vary in their propensity to recur or progress to invasive breast cancer. As a consequence, a significant proportion of patients diagnosed with DCIS can be treated adequately with breast-conserving therapy (i.e., excision with or without radiation therapy). Which patients with DCIS can be treated safely with excision alone and which patients require radiation therapy after excision is a pressing clinical question. Attempts to resolve this issue have focused on the identification of risk factors for local recurrence after breast-conservation therapy for DCIS. With three exceptions (the prospectively randomized NSABP B-17, the EORTC 10853, and the United Kingdom Coordinating Committee on Cancer Research [UKCCCR] trials), all such studies have been retrospective in design. Nonetheless, a number of factors have been identified that may be important in defining local failure risk. These include symptomatic presentation (15,87,116), lesion size (108,116), histopathologic subtype (15), nuclear/cytologic grade (87,116,119), central necrosis (87,116,119), margin status (109,116,117), and patient age (15,42,117,127).
The relative importance of any histopathologic factor in predicting the probability of local recurrence and, in turn, selecting the appropriate therapeutic option for a given patient is unclear. This is partly the result of the inherent difficulty associated with the establishment of standardized and reproducible systems of pathologic classification, including such apparently straightforward assessments of grade, margin width, and lesion size.
Recent efforts to classify DCIS have been based primarily on the nuclear grade of the lesion and/or the presence or absence of necrosis. A number of studies have shown that there is an association between high nuclear grade and/or necrosis and the risk of local recurrence and progression to invasion (87,116,119). Although the criteria for histologic grading systems have been published, there are limited data regarding the ability of pathologists to apply them in a reproducible manner.
Several studies have shown that the status of the microscopic margins appears to be important in predicting the likelihood of recurrence in the breast for patients with both invasive breast cancer and DCIS treated with breast-conserving therapy (109,116,117). However, there are numerous technical problems in the evaluation of margins of breast-excision specimens. First, if a specimen is removed in more than one fragment, the margins cannot be evaluated. Second, there is no standardized method for sampling or reporting margins, and this process is subject to sampling error. Finally, it is often difficult to provide an accurate assessment of the margin width for patients who undergo a re-excision as the initial biopsy site can be eccentrically located in the surgical specimen.
Most DCIS lesions present as a nonpalpable, grossly inapparent mammographic abnormality, which can make accurate determination of the size or extent of the lesion difficult (Fig. 52.5). The two modalities available to assess the size of the lesion are mammography and pathologic examination. Mammography frequently will underestimate the pathologic extent of DCIS, particularly for well-differentiated lesions in which substantial areas of the tumor may not contain microcalcifications. Pathologic assessment of lesion size also can be difficult. Macroscopic examination of a specimen containing DCIS rarely reveals a grossly evident tumor that can be measured. Therefore, the assessment of the size of the lesion must be estimated from histologic sections.
Studies performed during the past two decades clearly have suggested that DCIS is not a single disease. Rather, this term encompasses a diverse group of lesions that differ with regard to their clinical presentation, mammographic features, extent and distribution within the breast, histologic characteristics, and biologic markers. Moreover, clinical follow-up studies have indicated that these lesions vary in their propensity to recur or progress to invasive breast cancer. As a consequence, a significant proportion of patients diagnosed with DCIS can be treated adequately with breast-conserving therapy (i.e., excision with or without radiation therapy). Which patients with DCIS can be treated safely with excision alone and which patients require radiation therapy after excision is a pressing clinical question. Attempts to resolve this issue have focused on the identification of risk factors for local recurrence after breast-conservation therapy for DCIS. With three exceptions (the prospectively randomized NSABP B-17, the EORTC 10853, and the United Kingdom Coordinating Committee on Cancer Research [UKCCCR] trials), all such studies have been retrospective in design. Nonetheless, a number of factors have been identified that may be important in defining local failure risk. These include symptomatic presentation (15,87,116), lesion size (108,116), histopathologic subtype (15), nuclear/cytologic grade (87,116,119), central necrosis (87,116,119), margin status (109,116,117), and patient age (15,42,117,127).
The relative importance of any histopathologic factor in predicting the probability of local recurrence and, in turn, selecting the appropriate therapeutic option for a given patient is unclear. This is partly the result of the inherent difficulty associated with the establishment of standardized and reproducible systems of pathologic classification, including such apparently straightforward assessments of grade, margin width, and lesion size.
Recent efforts to classify DCIS have been based primarily on the nuclear grade of the lesion and/or the presence or absence of necrosis. A number of studies have shown that there is an association between high nuclear grade and/or necrosis and the risk of local recurrence and progression to invasion (87,116,119). Although the criteria for histologic grading systems have been published, there are limited data regarding the ability of pathologists to apply them in a reproducible manner.
Several studies have shown that the status of the microscopic margins appears to be important in predicting the likelihood of recurrence in the breast for patients with both invasive breast cancer and DCIS treated with breast-conserving therapy (109,116,117). However, there are numerous technical problems in the evaluation of margins of breast-excision specimens. First, if a specimen is removed in more than one fragment, the margins cannot be evaluated. Second, there is no standardized method for sampling or reporting margins, and this process is subject to sampling error. Finally, it is often difficult to provide an accurate assessment of the margin width for patients who undergo a re-excision as the initial biopsy site can be eccentrically located in the surgical specimen.
Most DCIS lesions present as a nonpalpable, grossly inapparent mammographic abnormality, which can make accurate determination of the size or extent of the lesion difficult (Fig. 52.5). The two modalities available to assess the size of the lesion are mammography and pathologic examination. Mammography frequently will underestimate the pathologic extent of DCIS, particularly for well-differentiated lesions in which substantial areas of the tumor may not contain microcalcifications. Pathologic assessment of lesion size also can be difficult. Macroscopic examination of a specimen containing DCIS rarely reveals a grossly evident tumor that can be measured. Therefore, the assessment of the size of the lesion must be estimated from histologic sections.
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The overall incidence of DCIS in the general population is unclear. In an attempt to address this question, a small number of autopsy studies have been reported. One series examined 185 randomly selected breasts from 101 women in which a subgross sampling technique was used (6) and one or more foci of DCIS were found in 6% of cases. A review of seven autopsy series of women not known to have breast cancer during life showed a median prevalence of DCIS of 8.9% (range, 0% to 14.7%) (132). The fact that some autopsy series document a greater incidence of DCIS in asymptomatic women than most clinical series suggests either the possibility that DCIS is either underdiagnosed or that many cases are not clinically significant.
A primary consideration in the natural history of DCIS is the risk of progression to invasive carcinoma. The published evidence on the clinical course of untreated DCIS is sparse because it has been recognized as a distinct entity for only a relatively brief period, having been considered rare before the widespread use of mammography and having been treated most frequently by mastectomy. Those cases for which long-term follow-up data are available were grossly palpable DCIS, a form that may not be equivalent to the mammographic DCIS that is seen more commonly today. The few published long-term follow-up studies of DCIS after only biopsy document an overall incidence of subsequent invasive carcinoma of more than 36% (13,25,80,101). Most of these subsequent malignancies occur within 10 years, although as many as one-third may develop after 15 years (13,101).
Women with DCIS in one breast are at risk for a second tumor (either invasive or in situ) in the contralateral breast (56); the rate at which such tumors develop is similar to that among women with primary invasive breast cancer, approximately 0.5% to 1% per year.
DCIS is a part of the breast/ovarian cancer syndromes defined by BRCA1 and BRCA2, with mutation rates similar to those found for invasive breast cancer (23). These findings suggest that patients with DCIS with an appropriate personal or family history of breast and/or ovarian cancer should be screened and followed according to the same high-risk protocols as developed for invasive breast cancer.
A primary consideration in the natural history of DCIS is the risk of progression to invasive carcinoma. The published evidence on the clinical course of untreated DCIS is sparse because it has been recognized as a distinct entity for only a relatively brief period, having been considered rare before the widespread use of mammography and having been treated most frequently by mastectomy. Those cases for which long-term follow-up data are available were grossly palpable DCIS, a form that may not be equivalent to the mammographic DCIS that is seen more commonly today. The few published long-term follow-up studies of DCIS after only biopsy document an overall incidence of subsequent invasive carcinoma of more than 36% (13,25,80,101). Most of these subsequent malignancies occur within 10 years, although as many as one-third may develop after 15 years (13,101).
Women with DCIS in one breast are at risk for a second tumor (either invasive or in situ) in the contralateral breast (56); the rate at which such tumors develop is similar to that among women with primary invasive breast cancer, approximately 0.5% to 1% per year.
DCIS is a part of the breast/ovarian cancer syndromes defined by BRCA1 and BRCA2, with mutation rates similar to those found for invasive breast cancer (23). These findings suggest that patients with DCIS with an appropriate personal or family history of breast and/or ovarian cancer should be screened and followed according to the same high-risk protocols as developed for invasive breast cancer.
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Alterations in the surrounding breast parenchyma may also be seen with DCIS. High-grade DCIS, in particular, has been associated with the breakdown of the myoepithelial cell layer and basement membrane surrounding the ductal lumen (28), proliferation of fibroblasts, lymphocyte infiltration, and angiogenesis in the surrounding stromal tissues (52,53). Whether these stromal changes reflect important steps that facilitate primary tumor transformation or secondary alterations in response to ductal epithelium that is being transformed is unknown. Quantitative changes in the expression of genes related to cell motility, adhesion, and extracellular-matrix composition, all of which may be related to the acquisition of invasiveness, occur as DCIS evolves into invasive carcinoma (5). Data suggest that DCIS represents a stage in the development of breast cancer in which most of the molecular changes that characterize invasive breast cancer are already present, although the lesion has not yet assumed a fully malignant phenotype. A final set of events, which probably includes gain of function by malignant cells and loss of function and integrity by surrounding normal tissues, is associated with the transition from a preinvasive DCIS lesion to invasive cancer. Most, if not all, clinically relevant features of breast cancer, such as hormone-receptor status, the level of oncogene expression, and histologic grade, are probably determined by the time DCIS has evolved (17,54,72,131).
An occult microinvasive tumor (one that does not exceed 0.1 cm in diameter) may be seen with some cases of DCIS. Such cases are classified as microinvasive breast cancer (115) and are generally treated according to the guidelines for invasive disease. Occult microinvasive tumors are most common in patients with DCIS lesions that are >2.5 cm in diameter (69), those presenting with palpable masses or nipple discharge, and those with high-grade DCIS or comedonecrosis (92,107).
An occult microinvasive tumor (one that does not exceed 0.1 cm in diameter) may be seen with some cases of DCIS. Such cases are classified as microinvasive breast cancer (115) and are generally treated according to the guidelines for invasive disease. Occult microinvasive tumors are most common in patients with DCIS lesions that are >2.5 cm in diameter (69), those presenting with palpable masses or nipple discharge, and those with high-grade DCIS or comedonecrosis (92,107).
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The estrogen receptor is present in 70% of DCIS but the rate of expression is higher in low-grade lesions (90%) than in high-grade lesions (25%). This association with histologic grade is reversed for the rate of overexpression of HER2/neu proto-oncogene and the p53 tumor suppression gene. Approximately 50% of all DCIS lesions have overexpression of HER2/neu, and in 25% the p53 tumor suppressor gene is also detected. Both of these molecular markers are noted in 20% of low-grade lesions but are present in approximately two thirds of high-grade lesions.
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