While breast cancer has been recognized as a disease process since the Egyptians described it in 3000 BC,1 treatment is generally thought to have originated with Dr. William Halsted. In 1894 with his publication “The Results of Operations for the Cure of Cancer of the Breast,”2 radical mastectomy (removal of the breast, muscle, and lymph nodes) was introduced as the mainstay of treatment for breast cancer. Halsted wrote, “I was led to adopt this procedure because, on microscopical examination, I repeatedly found when I had not expected it that the fascia was already carcinomatous, whereas the muscle was certainly not involved.” He then went on to say, “There are undoubtedly many surgeons still in active practice who have never cured a cancer of the breast.”
Fortunately, with improved understanding of the biology of cancer, specifically the hormonal aspect of breast cancer, along with the advent of mammography, treatment has evolved significantly since Halsted’s initial description of the morbid and disfiguring radical mastectomy. Breast cancer has paved the way in cancer research and treatment, and the majority of patients today can be cured. Advances in chemotherapy and radiation therapy have allowed for more limited surgery, creating the modern systemic, multidisciplinary approaches.
The first major change in therapy came in 1971 with initiation of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B04 Trial, which established total mastectomy (removal of only the breast) as equally effective for early breast cancer with the benefit of lower morbidity than radical mastectomy.3 This led to the NSABP B06 trial for invasive cancer and the NSABP B17 trial for DCIS, which demonstrated that lumpectomy plus radiation, today’s breast conservation therapy (BCT), is equivalent to more radical surgery.4,5 Breast surgery continued to scale down with the NSABP B32 trial establishing the role of the sentinel lymph node biopsy6 and the Z0011 trial eliminating need for axillary node dissection in women with early-stage breast cancer and one or two positive nodes.7
Advancements were also achieved in the area of systemic therapy. The NSABP B18 trial established the role of neoadjuvant therapy in breast cancer treatment,8 while the NSABP P1 and NSABP P2 trials introduced the use of hormonal therapy, namely, tamoxifen and raloxifene.9,10 Additional trials have led to improvements in chemotherapy and use of more targeted agents. Breast cancer therapy today would be unrecognizable to Dr. Halsted, and research continues to look for ways to provide individualized targeted treatment while minimizing morbidity and improving outcomes.
Breast cancer therapy has benefited from large, multinational trials with extended follow-up, made possible in large part by the NSABP consortium. Many of the trials described in this chapter began in the 1970s, and interval follow-up has now been published in several manuscripts. We present the long-term results when they are available, as 25-year data can build on, and occasionally contradict, results from shorter follow-up periods. Since many of these trials build on the hypotheses and early results of prior studies, the articles presented in this chapter are presented chronologically by recruitment dates, rather than by date of publication.
Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation.
Fisher B, Jeong J-H, Anderson S, Bryant J, Fisher ER, Wolmark N
NEJM. 2002;347(8):567–575.Takeaway Point: After 25 years of follow-up, this large randomized trial fails to demonstrate any survival advantage to radical mastectomy for women with invasive cancer and clinically positive or negative axillary nodes. It also fails to demonstrate a survival benefit to total mastectomy plus postoperative radiation compared to total mastectomy alone in patients with clinically negative nodes.
Commentary: The National Surgical Adjuvant Breast and Bowel Project (NSABP) is a clinical trial cooperative group established in 1958 to conduct large-scale clinical trials in breast and colorectal surgery. Its research has significantly shaped the current treatment of breast cancer with multiple important clinical trials. The NSABP B04 trial was the first landmark trial in breast cancer, initiated in 1971, and was the basis for moving away from Halsted’s radical mastectomy and toward less extensive surgery. This specific publication is an update to the original trial with 25 years of follow-up and maintains the original conclusion that there is no survival advantage to radical mastectomy (breast, chest wall muscles, and axillary lymph nodes) over total mastectomy (removal of breast and skin only) in breast cancer.
Introduction: Previously, the Halsted radical mastectomy was the standard of care for all stages of breast cancer. High morbidity and anecdotal reports of less extensive surgery led the NSABP to initiate the B04 study in 1971 to explore other operative approaches to treating breast cancer. Initial analysis of this cohort demonstrated differences in local control of disease, but no survival difference. This study presents the 25-year follow-up data.
Objectives: The aims of the study were to determine whether patients with either clinically negative or clinically positive axillary nodes who received local or regional treatments other than radical mastectomy would have outcomes similar to those achieved with radical mastectomy.
Trial Design: Multicenter randomized controlled trial.
Inclusion Criteria: Women with operable breast cancer with either clinically positive or negative nodes.
Exclusion Criteria: Secondary or metastatic disease.
Intervention: Randomized to either total mastectomy alone, total mastectomy plus irradiation, or radical mastectomy. Node-positive subjects received an additional boost as compared with node-negative subjects undergoing radiation therapy. No adjuvant systemic therapy was administered.
Primary Endpoint: First local regional or distant recurrence of tumor, contralateral breast cancer or a second primary tumor other than a tumor of the breast, and death without evidence of cancer.
Secondary Endpoints: Death due to breast or other cancer.
Sample Size: 1765 women were enrolled between July 1971 and September 1974. For those with clinically negative axillary nodes, one-third underwent radical mastectomy, one-third total mastectomy with regional radiation, and one-third total mastectomy alone. For the women with clinically positive nodes, half underwent radical mastectomy and the other half underwent total mastectomy and regional radiation.
Statistical Analysis: Kaplan–Meier survival curves for disease-free survival (DFS), distant disease-free survival (DDFS), relapse-free survival (RFS), and overall survival. Cox proportional hazards models. Nonparametric models, Gray’s K-sample test statistic.
Baseline Data: The three groups were well matched for baseline characteristics. Approximately 70% of women in each group were over 50 years of age at time of enrollment. Mean tumor diameter was 3.3 cm for patients with negative nodes and 3.7 cm for patients with positive nodes.
Node-Negative Disease: No significant difference is DFS, RFS, DDFS, or overall survival was observed among the three node-negative groups. The lowest cumulative incidence of local or regional recurrence was for women treated with mastectomy and radiation (p 0.002), although there was no significant difference between groups in cumulative incidence of distant recurrence. Overall, approximately 40% of women with clinically negative nodes who underwent radical mastectomy had tumor-positive nodes on pathology.
Node-Positive Disease: No significant different in DFS, RFS, DDFS, or overall survival between the two node-positive treatment groups. 81.7% of women with clinically positive nodes had breast cancer–related events within the first 5 years of follow-up.
Regardless of nodal status, most first events were related to distant recurrences of tumor and to deaths that were unrelated to breast cancer.
Conclusion: After 25 years of follow-up, there is no survival advantage from radical mastectomy over total mastectomy in the treatment of node-negative or node-positive breast cancer. Additionally, there is no advantage to postmastectomy radiation in patients with node-negative breast cancer. Finally, leaving occult positive nodes behind does not significantly increase the rate of distant recurrence or breast cancer–related mortality.
Limitations: Lymph nodes were sometimes found in specimens removed during operations designated as total mastectomy alone, which may skew results. Also, whereas the study was relatively large, subgroups were small, which may have limited the ability to detect significant differences with the addition of radiation therapy to total mastectomy.
Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer.
Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, Jeong J-H, Wolmark N
NEJM. 2002;347(16):1233–1241.Takeaway Point: After 20 years of follow-up, breast-conserving therapy with lumpectomy plus radiation continues to be adequate treatment for invasive breast cancer.
Commentary: The NSABP initiated the B04 trial (see a, above) in 1971 to resolve controversy over the surgical management of breast cancer. The 25-year findings showed no significant difference in survival between women treated with the Halsted radical mastectomy and those treated with the less extensive total mastectomy. The B06 trial, which began in 1973, sought to evaluate the efficacy of breast-conserving therapy in women with stage 1 or 2 tumors. Although no significant difference in survival was noted among the three groups (mastectomy, lumpectomy, lumpectomy plus irradiation), lumpectomy plus irradiation resulted in significantly lower ipsilateral breast tumor recurrence (IBTR) as compared to lumpectomy without breast irradiation regardless of nodal status. NSABP B06 continues to be the basis for recommending breast-conserving therapy today. Of note, a substantial proportion of events in the study occurred after 5 years of follow-up, emphasizing the need for long-term follow-up and outcomes.
Introduction: This study reports on the B06 trial, initiated in 1973 to evaluate the efficacy of breast-conserving surgery (lumpectomy with or without radiation) compared with total mastectomy in women with stages 1 and 2 breast tumors measuring 4 cm or less. Initial analyses had demonstrated no significant survival difference, but a decrease in ipsilateral recurrence associated with radiation was observed. The present study reports the 20-year follow-up data.
Objectives: To determine whether lumpectomy with or without radiation is as effective as total mastectomy for the treatment of stage 1 and 2 invasive breast cancer.
Trial Design: Multicenter randomized controlled trial.
Inclusion Criteria: Invasive breast tumors ≤4 cm in diameter with negative or positive nodes.
Exclusion Criteria: Stage 3 or 4 cancer.
Intervention: Women were randomly assigned to lumpectomy with or without 50 Gy (grey unit) radiation, or mastectomy. If tumor-free margins were unattainable, mastectomy was performed even if randomized to lumpectomy initially. Level I and II axillary nodes were removed with lumpectomy, and complete axillary dissection was performed with mastectomy.
Primary Endpoint: Disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival.
Secondary Endpoints: Local, regional, and distant recurrences in the ipsilateral breast. Diagnosis of a second cancer. Distant metastases after a local or regional recurrence. Tumors in the contralateral breast. Death without evidence of cancer.
Sample Size: 2163 women were enrolled between August 1976 and January 1984. 1852 (86%) had follow-up data available at 20 years. Women were randomized independent of nodal status to lumpectomy (n = 634), lumpectomy plus irradiation (n = 628), and total mastectomy (n = 589).
Statistical Analysis: Kaplan–Meier curves; log-rank tests, log-rank statistic, and log-rank subtraction; tests for heterogeneity, Cox proportional-hazards models, and Gray’s K-sample test statistic to determine significance.
Baseline Data: The three groups were similar in age, tumor size, and nodal status.
Outcomes: Incidence of recurrence in the ipsilateral breast 20 years after surgery was 14.3% for lumpectomy plus irradiation group and 39.2% for lumpectomy without irradiation (p < 0.0001); this difference was significant for women with positive and negative nodes. There were no significant differences in DFS (P=0.26), DDFS (P=0.034), or overall survival (P=0.57) among the three treatment groups. There was no significant difference in DDFS between the women in the two lumpectomy groups who had specimens with tumor-free margins.
Conclusion: After 20 years, mastectomy compared with lumpectomy plus or minus radiation results in no significant difference in DFS, DDFS, and overall survival. The addition of irradiation to lumpectomy significantly decreases the rate of ipsilateral breast recurrence.
Limitations: In this study, only women with positive nodes received chemotherapy and the regimen used at the time was older and less effective. For this reason, the incidence of recurrence in this study is higher than more current studies. All women also underwent some form of axillary dissection at time of surgery, whereas sentinel lymph node biopsy is the current standard of care for clinically node-negative disease.
Lumpectomy compared with lumpectomy and radiation therapy for the treatment of intraductal breast cancer.
Fisher B, Constantino J, Redmond C, Fisher E, Margolese R, Dimitrov N, Wolmark N, Wickerham DL, Deutsch M, Ore L, Mamounas E, Poller W, Kavanah M
NEJM. 1993;328(22):1581–1586.Takeaway Point: Lumpectomy plus breast irradiation significantly reduced the rate of second ipsilateral breast tumors (both invasive and noninvasive) compared to lumpectomy alone for localized ductal carcinoma in situ.
Commentary: In the 1980s, utilization of mammography lead to increased diagnosis of ductal carcinoma in situ (DCIS). Prior to this study, mastectomy was still the standard of care for DCIS. After results from the NSABP B06 trial shifted treatment for invasive cancer to lumpectomy, there was a push to test the outcome of breast conserving therapy in DCIS. This is the first large, multicenter trial to compare lumpectomy alone to lumpectomy plus radiation therapy in DCIS. The B17 trial showed significantly decreased rates of recurrence with the addition of radiation therapy and is the basis for including radiation therapy in DCIS treatment today, although this continues to be a subject of debate.
Introduction: Ductal carcinoma in situ is being diagnosed more frequently at a clinically undetectable stage with the advent of mammography. Previous studies on the incidence of recurrence after local excision are based on women with palpable tumors. Appropriate treatment for tumors that are not clinically detectable is uncertain.
Objectives: “To test the hypothesis that in women with localized ductal carcinoma in situ thought to have been completely removed, lumpectomy (or more accurately, local excision, since most women did not have a palpable mass) plus breast irradiation is more effective than local excision alone in preventing a second cancer in the ipsilateral breast.”
Trial Design: Multicenter randomized controlled trial.
Inclusion Criteria: Women receiving lumpectomy for noninvasive cancer identified either clinically or mammographically; tumors with both DCIS and lobular carcinoma in situ (LCIS) and multiple lesions were also included.
Exclusion Criteria: Clinically positive axillary nodes, positive nodes after axillary dissection, previous cancer (other than cervical or skin cancer), tumor-embedded microcalcifications on final pathology.
Intervention: After lumpectomy, women were randomly assigned to either ipsilateral breast irradiation (50 Gy at 10 Gy per week) or no radiation therapy. Randomization was stratified according to age (<49 or >49), axillary dissection (performed or not performed), tumor type (DCIS or DCIS+LCIS), and method of detection (clinically, mammographically, or both). The cohort of women randomly assigned to breast irradiation received therapy within 2 months postoperatively.
Primary Endpoint: Event-free survival as defined by the presence of no new ipsilateral or contralateral breast cancers, regional or distant metastases, or other cancers.
Secondary Endpoints: Death.
Sample Size: 818 subjects enrolled between October 1, 1985 and December 31, 1990; 790 were included in the final analysis with 391 receiving lumpectomy alone and 399 receiving lumpectomy plus radiation therapy.
Statistical Analysis: Women having no event occurring had percentages computed by the actuarial method with a life table estimate. A two-sided summary χ2 (log-rank) test was used to compare time before the occurrence of a first event. Multivariate proportional-hazards analysis was used to test for specific interactions.
Baseline Data: Baseline characteristics were balanced between the two groups.
Outcomes: Women treated with lumpectomy alone had significantly worse event-free survival at 5 years compared with lumpectomy plus radiation (73.8% vs. 84.4%, p 0.001). Radiation therapy reduced the incidence of ipsilateral breast cancer by 58.8% (p < 0.001). Ipsilateral invasive cancer incidence was 10.5% in lumpectomy patients as compared to 2.9% in those treated with lumpectomy and radiation therapy (p <0.001).
Conclusion: Radiation therapy after lumpectomy improves overall event-free survival as compared with lumpectomy alone in women with DCIS.
Limitations: Pathology analysis may differ between centers because of difficulty in differentiating between benign breast lesions and DCIS, between DCIS and LCIS, and between DCIS and invasive cancer associated with DCIS. Sampling error accounted for some of the limitations due to discordance in diagnosis.
Long-term outcomes of invasive breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS.
Wapnir IL, Dignam JJ, Fisher B, Mamounas EP, Anderson SJ, Julian TB, Land SR, Margolese RG, Swain SM, Costantino JP, Wolmark N
J Natl Cancer Inst. 2011;103(6):478–488.Takeaway Point: Radiation and tamoxifen in addition to breast-conserving surgery for treatment of DCIS reduce the rate of invasive breast tumor recurrence.
Commentary: Diagnosis of DCIS has increased dramatically over the past two decades because of the increased usage and improved resolution of mammographic techniques. The initial report of the NSABP B17 trial in 1993 showed similar overall 5-year survival for patients with DCIS when comparing mastectomy to lumpectomy alone (LO) or lumpectomy with radiation (LRT), although the addition of radiation decreased the rate of ipsilateral breast tumor recurrence (IBTR). This trial represents an update of the B17 trial after 15 years of follow-up, and the B24 trial, which randomized patients with DCIS undergoing lumpectomy plus radiation (LRT) to tamoxifen (TAM) or no tamoxifen. This update specifically focuses on the occurrence of invasive IBTR (I-IBTR) and its effect on survival in patients in both the NSABP B17 and B24 trials. An important key finding in this study was that half of all IBTR were invasive, which was associated with an increased mortality risk. It is this finding that has emphasized the need for local control of DCIS to prevent invasive recurrences. The study also found that radiation and tamoxifen in addition to lumpectomy significantly reduced the rate of I-IBTR. Overall, survival remained high for all treatment groups with DCIS.
Introduction: Ipsilateral breast tumor recurrence (IBTR) is the most common failure event after lumpectomy for DCIS. This study evaluated invasive IBTR (I-IBTR) and its influence on survival among participants in two NSABP randomized trials for DCIS. The NSABP B7 trial demonstrated a 60% lower risk of IBTR with lumpectomy followed by radiation compared with lumpectomy alone at 5 years. The B24 trial investigated the addition of tamoxifen to lumpectomy and radiation, and demonstrated an additional risk reduction. This study presents an update on those cohorts after 15 years of follow-up.
Objectives: To investigate the impact of I-IBTR on the long-term mortality of patients receiving breast-conserving treatments for DCIS.
Trial Design: Two multicenter randomized controlled trials.
Inclusion Criteria: Women with DCIS undergoing lumpectomy with clear margins in the B17 cohort with follow-up information available. B24 also allowed women with DCIS at the tumor margins.
Exclusion Criteria: Patients undergoing mastectomy or having primary invasive tumor.
Intervention: In the B17 trial, patients were randomized to lumpectomy plus radiation (LRT) or lumpectomy alone (LO). In the B24 trial, patients were randomized to LRT with either placebo or tamoxifen (TAM) for 5 years.
Primary Endpoint: I-IBTR.
Secondary Endpoints: DCIS-IBTR, contralateral breast cancers (CBC), second primary cancer, all-cause mortality, and breast-cancer-specific mortality.
Sample Size: B17 trial enrolled 818 patients between 1985 and 1990, 495 randomized to LO and 413 to LRT. B24 enrolled 1804 patients between 1991 and 1994, with 902 randomized to placebo and 902 to tamoxifen.
Statistical Analysis: Cause-specific hazard ratios using the Cox proportional-hazards model. Proportional-hazards assumption evaluated using Schoenfeld residual plots. Indicator variables in conjunction with a time-varying covariate were used in the hazard regression model.
Baseline Data: Patient and disease characteristics were similar between all groups. In B24, 25% of patients were reported as positive margins.
Outcomes: 46.3% of all IBTR events were noninvasive; 53.7% were invasive. Rate of contralateral breast cancer was similar in the LO and LRT groups but lower in the LRT + TAM group. Rate of second primary cancers was similar among treatment groups. LRT group showed 52% reduction in risk of I-IBTR compared with the LO group (p < 0.001). Tamoxifen in combination with radiation therapy (LRT + TAM) showed 32% reduction in risk for I-IBTR compared with LRT + placebo (p 0.025). Radiation therapy reduced incidence of I-IBTR at 15 years from 19.4% in LO to 8.9% in B17 LRT, and to 10% in the B5 LRT + placebo group. There was a twofold increase in risk of endometrial cancers in LRT + TAM group compared with the LRT + placebo group. Positive margin status in B24 trial carried a twofold increased risk of I-IBTR.
No statistically significant differences in the hazard of local, regional, or distant disease between LRT and LO groups.
Conclusion: 50% of all IBTR after treatment for DCIS is invasive cancer, which is associated with an increased risk of mortality. Radiation therapy and tamoxifen both decrease the rate of invasive breast tumor recurrences in women with DCIS.
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