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Effective Local Therapy and Long-Term Survival in Breast Cancer

Effective Local Therapy and Long-Term Survival in Breast Cancer

ABSTRACT: The causal link between local control and long-term survival in breast cancer has become clearer over the past few years. Although the prevalence of breast cancer is high, there has been a steady decline in breast cancer mortality since the early 1990s. Improvements in breast cancer–specific mortality are the result of greater emphasis on cancer screening and improved treatment modalities, principally the development of effective adjuvant systemic therapy. Adjuvant radiation therapy (RT) substantially reduces local recurrence rates, and this reduction is even greater when combined with systemic therapy. Randomized controlled trials and meta-analyses have shown that reducing local recurrence improves overall long-term survival following both mastectomy and breast-conserving therapy. Clinical and translational research has begun to shed light on new prognostic and predictive markers that can assist in the assessment of an individual patient’s risk of local recurrence without RT and the likelihood of a survival benefit with RT. The ability to appropriately tailor therapy to reduce local recurrence rates is vital toward continuing the decline in breast cancer mortality.

Breast cancer is the most commonly diagnosed cancer among women in the United States.[1] Since the early 1990s, breast cancer mortality has steadily declined,[2] and statistical modeling using a Bayesian approach attributes these declining mortality rates to both earlier diagnosis and more effective treatments.[3] The presentation of breast cancer in the early 20th century was dramatically different from what is seen today. At that time, women often presented with tumors that encompassed large portions of the breast and surrounding tissues. In modern times, most breast cancer presents as a small localized tumor, largely due to improvements in patient awareness and earlier detection due to breast cancer screening.

The management of breast cancer has also changed significantly over the past few decades. While surgical excision is still the mainstay of therapy, the morbidity of radical mastectomy has been replaced by the development of multidisciplinary management strategies that achieve high levels of local control and improved survival through the use of combined-modality therapy. Major advances in systemic therapy have occurred (not addressed here)—including a variety of hormonal therapies, combination chemotherapy, and most recently anti-HER2 therapy—that have been demonstrated in randomized clinical trials to improve survival.

Over time, decisions regarding local treatment have been influenced by theories formulated to explain the development of distant metastases. Dr. William Halsted, a surgeon at Johns Hopkins in the early 20th century, hypothesized that breast cancer begins as a local disease with subsequent contiguous spread from the primary site through lymphatics, first to regional lymph nodes and then to distant sites.[4] Therefore, his approach was the use of aggressive surgery in the form of the radical mastectomy—removal of the affected breast, pectoral muscles, and regional lymphatics—intended to control local disease and improve long-term survival.

The radical mastectomy remained the standard of care for decades, well into the 1970s. At about that time, Dr. Bernard Fisher and others noted that some tumors spread to distant sites despite good local control. Based on this observation and laboratory studies showing that axillary nodes did not act as a “barrier” to distant spread, a second model developed that focused on the systemic nature of breast cancer and its ability to metastasize to distant sites very early in the course of the disease. This led to a model designating breast cancer as two separate entities: tumors that remained localized and others that presented with “micrometastatic” systemic disease at the time of diagnosis.[5]

Based on this hypothesis, emphasis shifted away from aggressive local treatment toward the development of effective “adjuvant” systemic therapy. For reasons discussed below, a third hypothesis was developed, combining aspects of both the Halsted and Fisher models of breast cancer. This view held that breast cancer is a spectrum of disease extending from that which “remains local throughout its course to one that is systemic when first detectable.”[6,7]

The move away from the Halsted hypothesis led to attempts to replace mastectomy with breast-conserving therapy (BCT). This requires an understanding of the extent of breast cancer in the breast.[8] Studies of mastectomy specimens show that most tumors are multifocal.[9,10] Holland et al demonstrated that approximately 30% to 40% of patients with tumors less than 4 cm in diameter have foci of cancer 2 cm from the edge of the gross tumor, and 7% to 9% of these patients have additional foci of cancer cells 3 to 4 cm from the edge of the gross tumor.[9] Multiple studies of wide excision alone, even with negative margins, have found that 30% to 40% of women develop local recurrence, demonstrating the biologic importance of breast cancer multifocality.[11]

Radiation Therapy Improves Local Control

The National Surgical Adjuvant Breast and Bowel Project (NSABP) conducted two of the earliest randomized controlled trials in the United States that evaluated extent of surgical resection and use of adjuvant radiation therapy (RT). The B-04 trial compared mastectomy and axillary dissection to total mastectomy with and without chest wall and regional nodal RT and showed that RT substantially reduced local-regional recurrence after total mastectomy, but there was no significant difference in disease-free survival or overall survival among the three treatment arms at 25 years of follow-up.[12] The B-06 trial compared modified radical mastectomy to lumpectomy and axillary dissection with and without breast RT.[13] Again, the addition of RT to lumpectomy substantially reduced the local recurrence rate, but there was no significant difference seen in disease-free, overall, or distant metastasis-free survival with 20 years of follow-up.

These trials demonstrated that RT can be combined with more limited surgery to achieve comparable levels of local tumor control as with more extensive surgery. The failure to demonstrate a survival advantage with improved local tumor control was used to support the systemic theory and the conclusion that local treatment “does not impact on survival.” As discussed below, in retrospect, these two landmark studies did not have sufficient numbers of patients (statistical power) to rule out a small but clinically significant survival benefit.

TABLE 1
Randomized Controlled Trials of Breast-Conserving Surgery + RT ± Systemic Therapy

Importantly, the NSABP B-06 trial results suggest that in addition to controlling distant micrometastases, systemic therapy may also work to increase the effectiveness of RT. In the B-06 trial, patients treated with lumpectomy and RT only received chemotherapy if they had node-positive disease. For those node-positive patients who received lumpectomy, RT, and chemotherapy, the 12-year local recurrence rate was less than 5% compared with 10% in the node-negative patients treated with surgery and RT alone.[13] The effect of systemic therapy on local control when combined with RT after breast-conserving surgery (BCS) is demonstrated in a number of randomized controlled trials showing substantial reduction in local recurrence (see Table 1). In the NSABP B-13 trial, the addition of chemotherapy with methotrexate followed by fluorouracil (5-FU) decreased the 10-year rate of in-breast recurrences from 15.3% to 2.6% (P = .001).[14,15]

A similar effect on local control is seen with the use of hormonal therapy. In the B-14 trial, 1,062 women were randomized to tamoxifen vs placebo following lumpectomy and RT.[16] At 10 years, the in-breast recurrence was reduced from 10.3% to 3.4% with the addition of hormonal therapy (P < .001). A 6.5% absolute reduction in local recurrence at 8 years was seen with the addition of tamoxifen to RT in patients with early-stage cancer treated with BCS in the B-21 trial.[17] A 12% absolute reduction was seen in the Stockholm adjuvant tamoxifen trial.[18] These results show that systemic therapy substantially increases the effectiveness of RT following BCS.

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