Over the last four decades, there has been a paradigm shift in the management of breast cancer as a result of several landmark clinical trials conducted in the United States and Europe that are responsible for the new standards of breast cancer care worldwide. Advances from these clinical trials transformed the treatment of breast cancer by advocating less radical surgery and introducing the use of innovative techniques in conjunction with other modalities including systemic chemotherapy, endocrine therapy, and radiotherapy (RT). This subsequently led to a multidisciplinary approach to breast cancer and is further leading to individualized treatment for each patient. This chapter provides a review of the significant landmark clinical trials that revolutionized the management and that currently guide the surgical practice of noninvasive and invasive breast cancer.

Before the 20th century, breast cancer was considered a fatal disease with no available treatment options. The Halstedian radical mastectomy—the en bloc radical resection of the breast, overlying skin, pectoralis muscles, and axillary lymph nodes—provided a major advance in the treatment of the disease.¹ This aggressive surgical intervention was based on Halsted’s theory that cancer initially spread from tumor growth within the breast to the pectoralis muscles and regional lymph nodes and was followed by metastasis to distant sites. Investigators at the National Surgical Adjuvant Breast and Bowel Project (NSABP) began to question the Halsted theory in the late 1960s, and in 1971 challenged it with the initiation of the B-04 protocol, one of the most well-known and instrumental trials that altered surgical practice. The NSABP B-04 was designed 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.² A total of 1079 women with clinically negative axillary nodes underwent radical mastectomy, total mastectomy without axillary dissection but with postoperative RT, or total mastectomy plus axillary dissection only if their nodes became positive; 586 women with clinically positive axillary nodes underwent either radical mastectomy or total mastectomy without axillary dissection but with postoperative RT. Results showed that women with clinically negative nodes had a hazard ratio (HR) of 1.08 (95% confidence interval [CI], 0.91 to 1.28; P = 0.38) for death among those who underwent total mastectomy and RT compared to those who underwent radical mastectomy. In addition, the HR for death among those who underwent total mastectomy without radiation compared with those who underwent radical mastectomy was 1.03 (95% CI, 0.87 to 1.23; P = 0.72). In women with positive nodes, the HR for death among those who underwent total mastectomy and radiation compared to those who underwent radical mastectomy was 1.06 (95% CI, 0.89 to 1.27; P = 0.49).² Reports from the NSABP B-04 trial at 3, 5, and 10 years showed no statistically significant differences with respect to disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) among the three groups of patients.³ After 25 years of follow-up, the B-04 trial continues to demonstrate no statistically significant differences in long-term outcome between clinically node-negative patients who received radical mastectomy and those who received total mastectomy with or without nodal RT, or between clinically node-positive patients who received radical mastectomy and those who received total mastectomy with nodal RT.⁴ The findings of B-04 validated the hypothesis that radical mastectomy has no advantage and opened the door to a new era of treating breast cancer less radically and in a more multimodality arena.

Several other important observations and hypotheses emerged from the B-04 trial to further dispute the radical approach to early breast cancer. The next pivotal trial, NSABP B-06, compared lumpectomy and axillary node dissection with or without breast RT to modified radical mastectomy in patients with tumors 4 cm or less in their greatest diameter. Over 8 years, a total of 2163 women were randomly assigned to the trial. Patients were treated by lumpectomy with removal of sufficient normal breast tissue to ensure both tumor-free specimen margins and a satisfactory cosmetic result and subsequently received 50 Gy of RT without a boost administered to the breast but not to the axillary or other regional nodes. All women with one or more positive axillary nodes received adjuvant systemic therapy.² The HR for death among the women who underwent lumpectomy alone compared with those who underwent total mastectomy was 1.05 (95% CI, 0.90 to 1.23; P = 0.51), whereas the HR for death among those who underwent lumpectomy and breast RT compared with those who underwent total mastectomy was 0.97 (95% CI, 0.83 to 1.14; P = 0.74). Among the lumpectomy-treated women with tumor-free margins, the HR for death for those who underwent postoperative breast RT compared with those who did not was 0.91 (95% CI, 0.77 to 1.06; P = 0.23). The cumulative incidence of recurrent tumor in the ipsilateral breast was 14.3% in women who underwent lumpectomy and breast RT, compared with 39.2% in those who underwent lumpectomy alone (P < 0.001).² After 20 years of follow-up, there continues to be no statistically significant differences in OS, DFS, or DDFS between the group of patients who underwent total mastectomy and the group treated with lumpectomy alone, or with lumpectomy and breast RT.⁵ The trial continues to demonstrate the value of lumpectomy combined with breast RT and was instrumental in establishing that the preferred treatment in the majority of patients with invasive operable breast cancer was breast-conserving surgery (BCS) plus RT.

In addition to NSABP B-06, other clinical trials were conducted to investigate breast-conservation therapy as a safe therapeutic modality for breast cancer treatment. One such study to confirm the concept of breast-conserving therapy (BCT) coupled with the importance of RT as an adjunct included the group from the Milan Cancer Institute. From 1973 to 1980, the Milan I study⁶ compared the efficacy of radical (Halsted) mastectomy with that of BCS by randomly assigning 701 women with breast cancers measuring no more than 2 cm in diameter to undergo radical mastectomy (349 patients) or BCS (quadrantectomy) followed by radiotherapy to the ipsilateral mammary tissue (352 patients). Interestingly, the Milan study revealed that 30 women in the BCT group had a recurrence of tumor in the same breast, whereas 8 women in the radical-mastectomy group had local recurrences (P < 0.001). After a 20-year review, the cumulative incidence of the events was 8.8% and 2.3%, respectively. Of note, there was no statistically significant difference between the two groups in the rates of contralateral breast carcinomas (CBC), distant metastases, or second primary cancers. The Milan Trial concluded that the long-term survival rate for women who undergo BCS is the same as that for those who undergo radical mastectomy. This provided further evidence to support the idea that BCS should be the treatment of choice for women with relatively small breast cancers.

Randomized trials in the late 1970s to early 1980s established an important clinical benefit for the use of tamoxifen in the treatment of breast cancer. In 1982, the NSABP initiated Protocol B-14⁷ to compare postoperative tamoxifen (10 mg BID) with placebo administered in a double-blind design for breast cancer patients with ER-positive tumors and no evidence of axillary node involvement. The trial included 2644 patients with breast cancer, histologically negative axillary nodes, and ER-positive (greater than or equal to 10 fmol) tumors. There was no survival advantage observed during 4 years of follow-up (92% for placebo vs. 93% for tamoxifen; P = 0.3). On the contrary, there was a statistically significant prolongation of DFS among women treated with tamoxifen compared to the placebo patients (83% vs. 77%; P< 0.00001). Interestingly, this advantage was observed not only in patients 49 years and younger (P = 0.0005), whose rate of treatment failure was reduced by 44%, but also in those 50 and older (P = 0.0008). Multivariate analysis indicated that all subgroups of patients benefited, and tamoxifen statistically significantly reduced the rate of treatment failure at local and distant sites and tumors in the opposite breast, as well as the incidence of tumor recurrence after lumpectomy and breast RT; benefit was attained with a low incidence of clinically appreciable toxic effects. B-14 established that tamoxifen treatment is justified as effective therapy in prolonging DFS and survival in patients with negative nodes and ER-positive tumors.

Following the results from the B-06, B-14, and the Milan trials, more clinical trials were initiated to answer the unresolved question of whether all patients who had invasive breast cancer undergoing lumpectomy needed postoperative radiotherapy. It was postulated that radiotherapy could be safely omitted from the treatment of those who had small tumors (≤1  cm), due to lower rates of local recurrence. In addition, another argument at the time, introduced at the 1990 Consensus Development Conference, was that patients with negative nodes and tumors 1 cm or smaller might not need adjuvant systemic therapy, considering their overall good prognosis.¹ NSABP Protocol B-21⁸ was designed to include patients who had tumors 1 cm or smaller to adequately address the possible omission of RT and to evaluate the value of systemic therapy, tamoxifen, in this population. The protocol randomly assigned 1009 women who had node-negative invasive breast cancer 1 cm or less (T1a/b N0 M0) who were treated with lumpectomy followed by either tamoxifen (n = 336), or RT plus a placebo (n = 336), or RT plus tamoxifen (n = 337), with tamoxifen and the placebo being administered for 5 years. The study demonstrated that RT plus placebo resulted in a 49% lower hazard rate of ipsilateral breast tumor recurrence (IBTR) than did tamoxifen alone. Furthermore, RT plus tamoxifen resulted in a 63% lower rate than did RT plus placebo. RT combined with tamoxifen resulted in an 81% reduction in hazard rate of IBTR when compared with tamoxifen alone. The cumulative incidence of IBTR at 8 years revealed in this study was 16.5% with tamoxifen, 9.3% with RT plus placebo, and 2.8% with RT plus tamoxifen. It was noted that RT reduced IBTR below the level achieved with tamoxifen alone, regardless of ER status. Regarding contralateral breast cancers, when tamoxifen-treated women were compared with those who received RT plus placebo, there was a statistically significant reduction (HR, 0.45; 95% CI, 0.21 to 0.95; P = 0.039). Interestingly, survival in the three groups was 93%, 94%, and 93%, respectively (P = 0.93). NSABP B-21 confirmed that tamoxifen was not as effective as breast RT for locoregional control in node-negative patients with small invasive tumors treated by lumpectomy. It further validated that the combination of tamoxifen and breast RT results in better local control of the disease in the breast than either modality alone. The long-term results of follow-up (median, 11.2 years) continued to support the need for local breast RT and adjuvant therapy in the management of patients with these small breast cancers.⁹

As more randomized trials verified the value of BCS in patients with invasive breast cancer, the focus then shifted to a different population of breast cancer patients. With the widespread use of mammography in the 1980s also came a dramatic increase in the diagnosis of small, localized, nonpalpable ductal carcinoma in situ (DCIS), an entity with excellent prognosis after local therapy alone.² Based on the results of B-06 and other trials, during this time a paradox existed in the surgical treatment of early-stage breast cancer, with invasive disease being popularly and successfully treated with lumpectomy, but mastectomy remaining the recommended surgical treatment for noninvasive disease. The NSABP was the first group to investigate breast conservation as a potential treatment for DCIS in the NSABP B-17¹⁰ protocol. This prospective randomized trial compared lumpectomy alone to lumpectomy plus breast RT in 818 patients with localized DCIS.² The trial demonstrated that the cumulative incidence of noninvasive ipsilateral breast cancer recurrence as a first event was reduced with breast RT from 14.6% to 8.0% (P = 0.001). The cumulative incidence of invasive ipsilateral recurrence was also reduced from 16.8% to 7.7% (P = 0.00001). There was no difference in OS observed between the two groups (86% vs. 87%, P = 0.80).² In a 12-year review, tumor pathology features were analyzed with regard to their prognostic significance for ipsilateral breast cancer recurrence in a subset of patients.² The characteristic of moderate/marked comedo necrosis was a statistically significant independent predictor of risk for ipsilateral breast cancer recurrence in both treatment groups. After that 12-year follow-up, updated results from B-17 continue to indicate that radiotherapy significantly decreases the rate of invasive and noninvasive IBTR. Thus, this trial served to introduce BCS as a valid option for the treatment of noninvasive breast cancer.

The NSABP continued to invest efforts in establishing a multimodality regimen for the treatment of noninvasive breast cancer. The B-24 protocol¹¹ expanded on the B-17 experience, which established lumpectomy plus breast RT as the standard of care for resected, localized DCIS.¹ The B-24 trial was designed to evaluate the role of adjuvant tamoxifen therapy in patients previously treated with lumpectomy plus breast RT. Approximately 1804 patients with DCIS, including those with positive margins, were randomly assigned in a double-blind controlled study to the two arms of this trial: lumpectomy plus breast RT followed by 5 years of tamoxifen versus placebo. Through 12 years of follow-up, the findings continued to demonstrate that RT after lumpectomy reduces the incidence rate of all IBTRs by 58% and that the administration of tamoxifen after lumpectomy plus RT results in a statistically significant decrease in the rate of all breast cancer events, particularly in invasive cancer. B-24 also showed that the addition of tamoxifen significantly improved DFS from 77.1% to 83.0% (P = 0.002), and the cumulative incidence of all ipsilateral and contralateral breast cancer events was reduced by 39%, from 16.0% in the placebo group to 10.0% in the tamoxifen group (P = 0.0003). In addition, this trial found that all invasive breast cancer event rates were reduced 45% (P = 0.0009), and noninvasive breast cancer event rates were reduced 27% (nonsignificant, P = 0.11), all with the addition of tamoxifen.¹ The cumulative incidence of ipsilateral breast cancers after tamoxifen was reduced by 31% (11.1% with tamoxifen vs. 7.7% with placebo, P = 0.02), and the cumulative incidence of contralateral breast cancers was reduced by 47% (4.9% vs. 2.3%, P = 0.01). All the results from this study were critical in establishing that the combination of lumpectomy, RT, and tamoxifen was effective in the prevention of recurrent invasive cancer. More importantly, the B-24 trial was initiated before hormone receptor status was routinely evaluated in DCIS; the results suggested that routine assessment of ER status should be performed in patients who not only have invasive cancer but also in those with DCIS to determine their candidacy for tamoxifen therapy.¹

Local excision (LE) alone has been proposed as an option for selected patients with DCIS. Although attempts have been made to define a subset in which this procedure alone would be appropriate, clear-cut criteria have not been established. Factors that have been considered include extension of the lesion, no association with invasion, unicentricity, or a biologically unaggressive tumor. The ECOG E5194 study¹² prospectively defined a low-risk subset (low- to intermediate-grade (LIG) with DCIS greater than 0.3 cm but less than 2.5  cm and margins greater than 3 mm) of 671 patients treated with lumpectomy and whole-breast irradiation (WBI) or lumpectomy alone. In the high-grade DCIS, the rate of ipsilateral recurrence was 15.3%, suggesting that excision alone is associated with a high risk of local recurrence in those patients; in the LIG group, however, the 5-year rate of ipsilateral breast events (IBEs) was 6.1%. Similarly, RTOG 9804¹³ was a prospective randomized trial for “good risk” DCIS comparing RT to observation to determine the benefits of RT. Patients in both arms of the study were treated with tamoxifen. The addition of RT showed a statistically significant reduction in IBTR, with 5-year rates of 0.4% and 3.2% for the RT and observation arms, respectively.