Stages 0 and I Breast Cancer
Stages 0 and I Breast Cancer
This chapter focuses on the diagnosis and management of early-stage breast cancer, ie, stages 0 and I disease. This is an important area, since more noninvasive and small breast cancers are being diagnosed due to increasing use of screening mammography. Treatment of these malignancies will continue to evolve as the results of clinical trials lead to further refinements in therapy.
Stage 0 breast cancer includes noninvasive breast cancer—lobular carcinoma in situ (LCIS) and ductal carcinoma in situ (DCIS)—as well as Paget disease of the nipple when there is no associated invasive disease.
LCIS is nonpalpable, produces no consistent mammographic changes, and is often an incidental finding seen on a breast biopsy performed for another reason. The biologic behavior of LCIS continues to be an issue of debate. Most clinicians agree that it is a marker for increased risk of all types of breast cancer (both noninvasive and invasive).
Epidemiology and etiology
The incidence of LCIS has doubled over the past 25 years and is now 2.8 per 100,000 women. In the past, the peak incidence of LCIS was in women in their 40s. Over the past 3 decades, the peak incidence has increased to individuals in their 50s. The incidence of LCIS decreases in women who are in their 60s to 80s. The age of peak incidence of LCIS may be related to the use of hormone replacement therapy. It is also possible that use of hormone replacement therapy prevents the usual regression of LCIS normally seen at the time of menopause.
Signs and symptoms
LCIS is nonpalpable and has no consistent features on breast imaging. Most often, LCIS is found in association with a separate mammographic abnormality or palpable mass.
Risk of invasive cancer
Approximately 20% to 25% of women will develop invasive cancer within 15 years after the diagnosis of LCIS. More often, the invasive cancer is ductal in origin, and both breasts are at risk. At this point, there are no reliable molecular markers to determine which patients with LCIS will progress to invasive cancer.
Just as the incidence of LCIS has increased, there has also been an associated increase in the incidence of cases of infiltrating lobular carcinoma in postmenopausal women. The increase in invasive lobular carcinoma peaks in women in their 70s.
LCIS appears to arise from the terminal duct-lobular apparatus, and the disease tends to be multifocal, multicentric, and bilateral. Subsequently, other types of LCIS have also been described. One of these, pleomorphic LCIS, tends to be associated with infiltrating lobular carcinoma, and its cytologic features are similar to those of intermediate- or high-grade DCIS. Pleomorphic LCIS may be more aggressive and more likely to progress to invasion than classic LCIS.
The management of LCIS is continuing to evolve, since the disease appears to be heterogeneous. Presently, treatment options include close follow-up, participation in a chemoprevention trial, use of tamoxifen, or bilateral prophylactic total mastectomy with or without reconstruction. At present, the decision regarding a given treatment will depend upon the patient's individual risk profile for DCIS or invasive breast cancer, determined after careful counseling. In the future, treatment decisions may be based upon an analysis of a series of molecular markers, which can separate patients with a low risk for invasion from those who are at high risk for disease progression.
DCIS is being encountered more frequently with the expanded use of screening mammography. In 2012, an estimated 63,300 new cases of in situ breast cancer are expected to occur among women. Of these, approximately 85% will be DCIS. In some institutions, DCIS accounts for 25% to 50% of all breast cancers.
DCIS, like invasive ductal carcinoma, occurs more frequently in women, although it accounts for approximately 5% of all male breast cancers. The average age at diagnosis of DCIS is 54 to 56 years, which is approximately a decade later than the age at presentation for LCIS.
Parikh et al compared the clinicopathologic features and long-term outcomes from women with DCIS vs DCIS with microinvasion (DCISM) treated with breast conservation, to assess the impact of microinvasion. They concluded that natural history of DCISM closely resembles that of DCIS. The incidence of axillary metastasis in DCISM appears to be small (less than 3%) and does not appear to correlate with outcomes. Furthermore, the incidence of locoregional and distant failures in DCISM is low. Thus, microinvasion should not be the sole criterion for more aggressive treatment.
Signs and symptoms
The clinical signs and symptoms of DCIS include a mass, breast pain, or bloody nipple discharge. On mammography, the disease most often appears as microcalcifications. Because these microcalcifications are nonpalpable and are not always associated with a mass, DCIS is often discovered with mammography alone. Approximately 5% of patients who present with pathologic nipple discharge will have underlying breast cancer, and many of them will have DCIS alone.
Kuhl et al investigated the sensitivity of mammography vs magnetic resonance imaging (MRI) in detecting DCIS and compared the biological profiles of abnormalities detected by each method. Over a 5-year study period, 198 women had a pathologic diagnosis of pure DCIS without associated invasive breast cancer or microinvasion. In all, 167 of these women underwent both imaging tests preoperatively; 93 (56%) of these cases were diagnosed by mammography, and 153 (92%) were diagnosed by MRI (P < .001). The sensitivity of mammography decreased with nuclear grade; it was highest in patients with low-grade DCIS and lowest in cases of high-grade DCIS. The sensitivity of MRI was superior to that of mammography across all DCIS subtypes. In addition, sensitivity increased with nuclear grade of DCIS; it was lowest in low-grade cases (80%) and highest in high-grade cases (98%), independent of the presence or absence of necrosis.
Risk of invasive cancer
The risk of developing an invasive carcinoma following a biopsy-proven diagnosis of DCIS is between 25% and 50%. Virtually all invasive cancers that follow DCIS are ductal and ipsilateral, and they generally present in the same quadrant within 10 years of the DCIS diagnosis. For these reasons, DCIS is considered a more ominous lesion than LCIS (which is considered a marker for risk) and appears to be a more direct precursor of invasive cancer.
A variety of histologic patterns are seen with DCIS (eg, solid, cribriform, papillary). Some researchers have divided DCIS into two subgroups: comedo and noncomedo types. As compared with the noncomedo subtypes, the comedo variant has a higher proliferative rate, overexpression of HER2/neu, and a higher incidence of local recurrence and microinvasion. DCIS is less likely to be bilateral and has approximately a 30% incidence of multicentricity.
Ductal carcinoma in situ
Breast-conserving surgery. Breast-conserving surgery, followed by radiation therapy to the intact breast, is now considered the standard treatment of DCIS. Because the incidence of positive lymph nodes after axillary lymph node dissection for DCIS is about 1% to 2%, neither sentinel node nor axillary dissection is indicated in most instances.
The most important factor in determining local tumor control within the breast is margin status. A surgical margin of 1 mm has been associated with a 43% chance of having residual disease at the time of reexcision. When a surgical margin of 10 mm can be obtained, there is an extremely low rate of recurrence (4%). A 10-mm surgical margin may not be practical, however, when trying to provide a good cosmetic outcome. When breast-conserving therapy is used alone (without irradiation), a margin of at least 10 mm is required, and the tumor should be small (< 1 cm) and a noncomedo type. Although a wide margin is always desirable, narrower margins are acceptable for DCIS when radiation therapy is used after lumpectomy. Recent data suggest that a 2 mm margin is adequate when lumpectomy is combined with radiation therapy.
Sentinel node biopsy. The sentinel lymph node is the first node in the draining lymphatic basin that receives primary lymph flow. Sentinel lymph node biopsy represents a minimally invasive way to determine whether the axilla is involved with disease.
When blue dye is used, it can be injected into the breast parenchyma at the primary tumor or subareolar site. The radioactive tracer can be injected subdermally or intraparenchymally at the site of the primary tumor or in the subareolar location. The site and technique of injection will be based upon individual patient factors, including the type and location of the previous breast biopsy.
When lymphatic mapping and sentinel lymph node biopsy are performed, a blue vital dye and/or a radioactive tracer (generally technetium-labeled sulfur colloid) can be used. When a radiotracer is used, lymphoscintigraphy can also be performed to aid in locating the sentinel node. When a sentinel node biopsy is performed using blue dye, the axillary surgery should be performed carefully to avoid disrupting the blue-stained afferent lymphatic channels. When a radioisotope is used, a handheld gamma counter is used to locate the sentinel node.
Axillary lymph node dissection is not routinely recommended for patients with DCIS. Recently, however, investigators have used sentinel lymph node biopsy to determine whether individuals with DCIS may harbor occult nodal metastases. Current studies have identified metastatic disease to the axillary nodes in up to 12% of patients who have undergone sentinel lymph node biopsy. Despite this relatively high percentage of positive sentinel nodes, recurrence in the nodal basins is rare (about 2%). Based on this and recent work, there is no indication for routine sentinel lymph node biopsy in patients with DCIS.
Factors associated with an increased risk of axillary metastasis with a diagnosis of DCIS are DCIS that is so extensive as to require mastectomy, suspicion of microinvasion, DCIS associated with a palpable mass, and evidence of lymphovascular permeation or invasion seen on review of the slides. These factors likely are associated with a preoperatively nondiagnosed invasive component. For patients diagnosed with DCIS who are scheduled for mastectomy, however, sentinel lymph node biopsy is a reasonable practice. In the event that an occult invasive cancer within the mastectomy is found, a negative sentinel node would make it possible to avoid axillary dissection.
Sentinel lymph node biopsy is discussed below and axillary node dissection following sentinel node biopsy is discussed further in the "Stage II Breast Cancer" chapter.
Adjuvant radiation therapy. Retrospective series have analyzed data on patients with DCIS, as well as subsets of patients with early invasive cancer, treated with conservative surgery alone, omitting radiation therapy to the intact breast. In addition, several prospective, randomized trials have attempted to address this issue of omission of breast irradiation for both invasive cancer and DCIS. It is clear from all of these series that omission of breast irradiation results in a significantly higher ipsilateral breast tumor recurrence rate but that it has not, as yet, had an impact on overall survival.
Two large, prospective, randomized trials have demonstrated a significant reduction in local relapse with the use of postlumpectomy irradiation in treatment of DCIS. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-17 trial, the local recurrence rate at 8 years was reduced from 27% to 12% with postlumpectomy irradiation.
Similar results have been reported by a European cooperative group study of 1,010 women with DCIS who were randomly assigned to receive either 50 Gy of radiotherapy to the whole breast over 5 weeks or no further treatment. With a median follow-up of 4.25 years, the 4-year local relapse-free rate was 91% in the radiotherapy arm vs 84% in the observation arm. Hazard ratios (HRs) with postexcision radiotherapy were 0.62 for all local relapses, 0.65 for DCIS recurrences, and 0.60 for noninvasive recurrences.
Both trials showed that radiotherapy reduces the risk of both noninvasive and invasive recurrences. Identification of a subgroup of patients who did not benefit from postlumpectomy irradiation has not as yet been clearly defined.
The Van Nuys Predictive Index (VNPI), based on tumor size, grade, presence of necrosis, and width of the excision margin, is an algorithm commonly used to predict local recurrence after breast-conserving surgery with and without radiation for DCIS. In some series, VNPI lacked discriminatory power for guiding further patient management. In studies performed by this group, the width of the excision margin apparently was the most important predictor of local recurrence after breast-conserving surgery for DCIS.
One study demonstrated acceptable local control in patients with DCIS treated by excision alone, provided that wide negative margins were obtained. In this retrospective series of 469 patients, radiation therapy did not lower the local recurrence rate in patients with wide (≥ 10 mm) negative margins but did produce a significant benefit in patients with close (≤ 1 mm) margins. The authors concluded that radiation therapy is unlikely to benefit patients with wide negative margins and small tumors. However, adjuvant radiotherapy was omitted in a single-arm, prospective study of patients with grade 1 or 2 DCIS having a mammographic extent < 2.5 cm and treated with wide excision with final margins ≥ 1 cm. This trial was closed early, because the number of local recurrences met the predetermined stopping rules. The 5-year rate of ipsilateral breast tumor recurrence was 12%. Thus, the benefit of radiotherapy is still seen in traditionally low-risk patients.
Although there may be some patients for whom wide excision alone is appropriate therapy, no specific subgroup has been identified consistently in the available literature. Clearly, the omission of radiation therapy in subsets of patients remains a controversial issue worthy of further investigation. It is hoped that ongoing randomized studies will help to resolve some of the conflicts generated by selective, retrospective studies.
Two trials have addressed the need for postlumpectomy radiation therapy in older women with breast cancer. Both studies randomized patients, following lumpectomy and adjuvant hormonal therapy, to receive radiotherapy or observation. Both studies confirmed statistically significant improvements in local control with radiation therapy, and local relapse rates were acceptable in carefully selected patients. The authors concluded that selected elderly patients may be treated with hormonal therapy alone (without radiotherapy) following breast-conserving therapy.
Hughes et al published a prospective, nonrandomized study on behalf of the Eastern Cooperative Oncology Group (ECOG), E5194, which tried to determine the risk of ipsilateral breast events in patients with DCIS treated with local excision without irradiation. Eligible patients were those with either low- or intermediate-grade DCIS measuring 2.5 cm or smaller, or high-grade DCIS measuring 1 cm or smaller who had microscopic margin widths of 3 mm or wider and no residual calcifications on postoperative mammograms. At 10-year follow-up, ipsilateral breast recurrence rates of DCIS for patients with low- or intermediate-grade DCIS was 15.4%, and for high-grade DCIS was 15.1%. Recurrence with invasive breast cancer occurred in 5.6% of patients with low- or intermediate-grade DCIS and in 9.8% of patients with high-grade DCIS. The authors concluded that new methods for analyzing recurrence risk would be helpful in determining the need for adjuvant breast irradiation after wide excisions. Tissue samples were available from 49% of patients in the study, and those samples were analyzed using a quantitiative multigene reverse transcriptase polymerase chain reaction (RT-PCR) assay. A DCIS recurrence score was designed which was able to predict the likelihood of recurrence and complements the traditional and pathologic factors used to identify patients with DCIS who may be treated with wide excision alone. Goyal et al investigated the ipsilateral breast tumor recurrence (IBTR) in DCIS patients treated with brachytherapy in the MammoSite registry trial. A total of 194 patients with DCIS were treated, 70 of whom met criteria for the E5194 study. In contrast to the findings from E5194, the 5-year IBTR was lower at 0% and 5.3% for the low/intermediate grade (n = 41) and high-grade cohort (n = 29), respectively. The overall 5-year IBTR was 2%, with a median follow-up of 52.7 months.
Hughes et al previously reported the results of surgical excision (≥ 3 mm negative margins) without irradiation for selected patients with DCIS in ECOG E5194, where the 5-year rates of local recurrence varied with age, grade, and lesion size. To provide more accurate and reproducible assessment of recurrence risk, Solin and colleagues performed the Oncotype DX assay on samples from 327 patients (49% of the parent study) in E5194. A new, prespecified DCIS Score was designed to predict recurrence using an optimized gene expression algorithm. The primary objective was to determine whether there was a significant association between the risk of an ipsilateral breast event (IBE) and the continuous DCIS Score in Cox models. A total of 46 patients had an IBE (defined as ipsilateral local recurrence of DCIS [n = 20] or invasive cancer [n = 26]). Median follow-up was 8.8 years. The 10-year IBE rates were 15.4% for low- or intermediate-grade DCIS and 15.1% for high-grade DCIS (as determined by central pathology review), and for invasive IBE, 5.6% and 9.8%, respectively. Continuous DCIS Score was significantly associated with IBE (HR 2.34 per 50 units; 95% CI, 1.15–4.59; P = .02) when adjusted for tamoxifen use and with invasive IBE (HR 3.73; CI, 1.34–9.82; P = .01). DCIS Score was significantly associated with outcome when evaluated by the prespecified risk groups. Similar results were observed with and without adjustment for tamoxifen use or for negative margin width. Features associated with IBE in multivariate models included menopausal status (HR 0.49; 95% CI, 0.27–0.90; P = .02), tumor size (HR 1.52 per 5 mm; 95% CI, 1.11–2.01; P = .01), and continuous DCIS Score (HR 2.41; 95% CI, 1.15–4.89; P = .02). The authors concluded that the DCIS Score provides a new clinical tool for individualized selection of treatment for patients with DCIS (Solin L et al: 34th SABCS, 2011. Abstract S4-6).
Adjuvant trastuzumab therapy. Overexpression of HER2/neu is seen in more than 50% of cases of DCIS. It has been associated with high-risk disease (young age, estrogen receptor-negative status, high nuclear grade). The NSABP has opened a clinical trial in which patients with DCIS that is HER2/neu-positive who have undergone wide excision with negative surgical margins will be randomized to receive whole breast irradiation (WBI) alone vs WBI and two doses of trastuzumab (Herceptin) at weeks 1 and 4. Patients who are estrogen- and/or progesterone-positive will receive 5 years of hormone therapy. The goal of the study is to determine whether the addition of trastuzumab can prevent an IBTR.
Adjuvant tamoxifen therapy. Adjuvant chemotherapy is not routinely employed for patients with DCIS. In the NSABP B-24 trial, 1,804 women with DCIS treated with lumpectomy and irradiation were randomly assigned to receive placebo or tamoxifen. At a median follow-up of 74 months, women in the tamoxifen group had fewer breast cancer events than did those in the placebo group (8.2% vs 13.4%; P = .0009). Tamoxifen decreased the incidence of both ipsilateral and contralateral events. The risk of ipsilateral invasive cancers was reduced by tamoxifen, regardless of the presence or absence of comedo-necrosis or margin involvement.
In a more recent analysis of NSABP B-24, the benefit of tamoxifen was derived exclusively from patients with hormone receptor-positive disease. The pros and cons of tamoxifen should be discussed for the prevention of secondary breast cancers in women at high risk for breast cancer, such as women diagnosed with DCIS.
Wapnir et al analyzed data from 2,615 women with primary DCIS who participated in the NSABP B-17 and B-24 trials for IBTR; patients were followed for a median of > 12 years. IBTR was a first failure in 465 patients (243 invasive, 222 noninvasive). The 12-year cumulative incidence of all such recurrences was 32.9% for lumpectomy only, 15.8% for lumpectomy with WBI, and 12.5% for lumpectomy with WBI plus tamoxifen. Radiotherapy significantly reduced invasive IBTR. Tamoxifen conferred additional benefit in reducing invasive recurrences of this type. Women with invasive IBTRs had a twofold greater mortality risk relative to those who did not; the effect was greater for patients who underwent lumpectomy followed by WBI than for those who underwent only lumpectomy. Overall mortality was low and primarily due to development of IBTR. The investigators concluded that occurrence of an invasive IBTR after DCIS, and particularly after radiotherapy, confers increased risk for subsequent mortality, as seen after an invasive index tumor.
For nearly two decades there has been controversy regarding the role of radiation therapy in women over the age of 70 years with small breast cancers. The CALGB 9343 trial enrolled women over age 70 with clinically node-negative disease, who had undergone lumpectomy with a clear margin (1-cm negative margin), had a tumor size of 2 cm or less, and were ER-positive or of indeterminate status. These women were randomized to either tamoxifen or tamoxifen plus radiation. The 631 eligible patients were followed for a median of 12 years.
Radiation therapy was found to have an impact on breast tumor recurrence, with 6 events occurring in the 317 women who received tamoxifen plus radiation, compared with 27 events in 319 women who did not receive radiation (2% vs 9%, P < .001). However, there were no benefits in terms of ultimate mastectomy (2% with radiation vs 4% without, P = .1779), axillary recurrence (0% with vs 3% without radiation), the frequency of second primary cancers (12% vs 9%, P = .7268), or overall survival at 10 years (33% of patients in each treatment arm had died at 10 years, P = .845). To date, approximately 50% of the women are still alive, 3% have died from breast cancer, and 46% have died from other causes. It is notable that approximately 50% of women who were over 70 years of age upon enrollment in this study are still alive 12 years later. The investigators concluded that in older women the benefits of radiation after lumpectomy are small and that omitting radiation in women over 70 years of age with clinical stage I breast cancer is a reasonable alternative.