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 While surgical excision is still the mainstay of therapy, the morbidity of radical mastectomy has been replaced by the development of multidisciplinary management strategies that achieve high levels of local control and improved survival through the use of combined-modality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.

Importance of Local Control to Overall Survival

Mounting evidence suggests that the systemic model of breast cancer is not applicable to all patients with breast cancer. The reduction in breast cancer mortality by screening mammography and earlier diagnosis[19] provides support that breast cancer does not always begin as a systemic disease. A meta-analysis of eight randomized-controlled trials evaluating efficacy of mammographic screening demonstrated that screening mammography significantly reduces breast cancer mortality (relative risk [RR] 0.84; 95% confidence interval 0.77–0.99) compared to unscreened populations.[20] According to a recent analysis of the Surveillance Epidemiology and End Results database, between 1990 and 2003 breast cancer mortality among women of all ages decreased 24%.[21] Modeling techniques suggest that approximately half of this reduction is directly attributable to the increased use of screening mammography.[19]

The landmark Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) “Oxford” meta-analysis was the first study to convincingly demonstrate a causal link between reduction in local recurrence and improvements in long-term survival in women with breast cancer.[11] This meta-analysis included 42,000 patients in 78 randomized controlled trials from 1975 to 1995 that compared outcomes for different types of local therapy in the treatment of breast cancer. Comparisons included BCS or mastectomy, with or without RT, and more- vs less-extensive surgery. The great strength of this study is the very large number of patients with long follow-up that allowed for the detection of small but clinically important differences in long-term survival. The majority of the individual trials themselves did not provide the statistical power required to demonstrate a modest yet clinically meaningful improvement in long-term survival.

FIGURE 1

Summary of Effect of RT on Local Control and Mortality Following Breast-Conserving Surgery

The simple but elegant underlying concept of the EBCTCG analysis was that any effect on long-term survival had to be mediated by a reduction in local recurrence. Specifically, the study analyzed the relationship between absolute reductions in 5-year local recurrence and absolute reductions in 15-year breast cancer and overall survival. Table 2 briefly summarizes the major findings of the analysis with regard to the use of RT. For patients undergoing BCS, an 18.6% absolute reduction in 5-year local recurrence with the addition of RT resulted in a 5.4% absolute reduction in breast cancer–specific mortality and a 5.3% absolute reduction in all-cause mortality at 15 years (see Figure 1). Similarly, in women with node-positive disease who received postmastectomy RT (PMRT), a 17.1% absolute reduction in local recurrence resulted in a 4.4% absolute decline in all-cause mortality. These data formed the basis of the “4:1 ratio”; ie, for every four local recurrences prevented at 5 years, one death is prevented at 15 years. This ratio suggests that in approximately 25% of breast cancers that recur locally, a subset of the recurrent cells have acquired the capacity for distant spread.[22-24]

TABLE 2

Summary of Results From the EBCTCG Oxford Meta-Analysis

The causal relationship between local control and survival is strengthened by two factors. First is the time course of the effect. The survival benefit was not seen at 5 years and only emerged after 5 years further, suggesting a link between the local recurrence itself and long-term survival. Second, the meta-analysis showed a proportional correlation between the absolute reduction in the 5-year risk of local recurrence and the absolute reduction in 15-year breast cancer mortality. In women undergoing BCS for node-negative disease, RT resulted in a 16% absolute reduction in local recurrence and a 5.1% reduction in breast cancer mortality (P = .006). In cases of node-positive disease, a 30.1% reduction in local recurrence with the use of adjuvant RT resulted in a 7.1% reduction in mortality (P = .01). Similar absolute gains were seen following PMRT. In node-positive patients, a 17.1% absolute decrease in local recurrence with adjuvant RT yielded a 5.4% absolute reduction in breast cancer mortality (P < .001). The EBCTCG results consistently demonstrated that treatments that significantly reduce the absolute risk of local recurrence have a proportional effect on reductions in long-term mortality.

Another important contribution of the EBCTCG is in helping to delineate the relationship between RT dose/volume to the heart and late cardiac mortality. In the EBCTCG’s preliminary analysis, mean cardiac doses larger than 5 Gy were associated with discernible increases in late cardiac deaths (S. Darby, personal communication, 2009). It should be stressed, however, that this relationship was largely established in the absence of adjuvant systemic therapeutic agents such as doxorubicin and trastuzumab (Herceptin), which are known to cause cardiac toxicity. When external beam techniques are used it is critical that CT simulation be performed, during which the heart should be contoured so the RT dose/cardiac volume relationship can be determined.[25] A number of techniques are available to minimize cardiac dose both after BCS and mastectomy; these can be employed to maximize long-term survival.[26]

Refinements to the 4:1 Ratio

The 4:1 ratio has been well established in clinical practice to estimate the survival benefit of adding RT, particularly in the postmastectomy setting. It is worth noting, however, that the 4:1 ratio is an average effect that is largely based on trials without systemic therapy and does not account for the interrelated issues of (1) competing risks of local recurrence and distant metastases, (2) the impact of (improving) systemic therapy, and (3) biologic heterogeneity. If the ratio becomes less than 4:1, it means that local treatment is even more important for long-term survival.

The impact of competing risks of local recurrence (LR) and distant metastases (DM) is illustrated in a recent reanalysis of the Danish PMRT trials.[27] All patients underwent mastectomy and the premenopausal cohort (82b) received CMF (cyclophosphamide, methotrexate, 5-FU) chemotherapy,[28] while the postmenopausal cohort (82c) received 1 year of tamoxifen.[29] Patients were then randomized to PMRT vs observation. Both trials showed improvements in local recurrence rates and overall survival with the addition of RT. A total of 1,000 patients were grouped into good-, intermediate-, or poor-risk cohorts in the absence of PMRT based on the number of positive nodes, tumor grade, hormone and HER2 receptor status, and tumor size. Mortality rates were determined within each prognostic subgroup based on the reduction in local recurrence following PMRT (see Table 3).

TABLE 3

Outcomes Following Postmastectomy Radiation Therapy in Prognostic Groups in the Danish Trials

For the good-prognosis group, an 11% absolute reduction in the 5-year rate of LR following PMRT was associated with an 11% reduction in 15-year breast cancer mortality (33% vs 22%), resulting in a 1:1 ratio. A 21% absolute reduction in the 5-year rate of LR in the intermediate group was also associated with an 11% decrease in breast cancer mortality at 15 years (61% vs 50%), a ratio of 2:1. The largest absolute reduction in LR of 36% was seen in the poor-prognosis group, with a reduction in the 5-year LR rate from 50% to 14% following PMRT. Despite the large reduction in LR, mortality rates were the same (81%).

These results indicate that an appreciation of the competing risks of LR and DM is needed to assess the actual ratio. In patients at very high risk of DM, reductions in local recurrence will not result in a 4:1 survival benefit. This analysis suggests that PMRT might, in fact, be most appropriate for patients who have at least a moderate risk of local recurrence and only a small or moderate risk of DM.

Treatment effect also depends on biologic subtype. This point is illustrated in recent results from our institution.[30] In this study, hormone and HER2 receptor status was used as a surrogate for breast cancer subtype; we asked the question of whether subtype is associated with local recurrence after BCT. The study included 793 consecutive women who received lumpectomy and adjuvant RT for early-stage invasive breast cancer from 1998 to 2001. Ninety percent (90%) of patients received adjuvant systemic therapy, but during this time period, patients did not receive adjuvant trastuzumab.

The 5-year incidence of LR (in-breast recurrence) was 1.8% for the entire cohort illustrating the high rate of local control with BCT in an era of routine detailed preoperative imaging, careful pathologic review, and routine use of adjuvant systemic therapy. However, the local control rates varied by subtype. The 5-year LR rate was 0.8% and 1.5% in the luminal A and luminal B subtypes, respectively. In contrast, the HER2 and basal subtypes had LR rates of 8.4% and 7.1%, respectively. The very low rate of LR in the patients with luminal cancers represents the inherent biology of these cancers and the very favorable interaction between RT and hormonal therapy in reducing local recurrence.

TABLE 4

Local Recurrence Rates by Breast Cancer Subtypes Following RT After Breast-Conserving Surgery and After Mastectomy

The influence of breast cancer subtypes on local control was also seen in the postmastectomy setting in the Danish PMRT trials.[28,29] A subgroup analysis of the Danish trials was performed to determine whether subtype may be predictive of local recurrence and overall survival after PMRT.[31] The analysis included 1,000 women and subgroups were constructed based on hormone receptor status, as was done in the Nguyen study. In the Danish trial, basal or triple-negative and HER2 subtypes were the strongest predictors of local-regional recurrence, outperforming nodal status and tumor size. The results in the PMRT setting are similar to those found at our institution following BCT (see Table 4). Of note, the ratios of reduction in 5-year LR and 15-year mortality based on tumor subtype (see Table 5) are much better than the 4:1 ratio described in the Oxford meta-analysis.[11] The luminal cancers have ratios in the range of 1.5:1 to 2:1; results are even better for the basal group, with a 1:1 ratio. This suggests that the 4:1 ratio does not apply in all breast cancer subtypes, particularly with the use of adjuvant systemic therapy.

TABLE 5

Ratio of Local Recurrence/ Mortality by Subtype in the Danish Trials

The current data suggest that with increasingly effective systemic therapy, the risk of LR will be less, but the ratio will also be less. Current systemic therapy is most effective in the setting of microscopic residual disease or micrometastases. As systemic therapies are better able to sterilize distant disease, improvements in local-regional control have become more important. As systemic therapy continues to improve such that it can control both distant and local-regional disease, the eventual goal is that local therapy could be completely eliminated; however, that is likely to be sometime well into the future.[21]

One also has to consider the possible complications of RT. The long-term data from the EBCTCG show the use of RT results in a small increase in contralateral breast cancer (RR = 1.18), which can be reduced by techniques that minimize scatter dose to the opposite breast. Minimizing such scatter dose is particularly important in younger patients (aged < 45 years), who are known to be more susceptible than older patients to breast cancer carcinogenesis with irradiation. In the trials of RT after breast-conserving surgery, the 15-year breast cancer mortality and 15-year overall mortality gains were essentially the same (5.4% and 5.3%, respectively), while in the older trials of RT after mastectomy, the 15-year overall mortality gain was 1% to 3% less than the 15-year breast cancer mortality gain indicating some non–breast cancer mortality secondary to RT. In these older trials of PMRT, there was considerable cardiac irradiation and the excess non–breast cancer mortality was mainly attributable to an excess in cardiac mortality. Fortunately, the modern treatment techniques that reduce cardiac dose have been shown to reduce excess cardiac mortality substantially. The EBCTCG data also show a small increase in lung cancer with RT, and RT for breast cancer is known to cause secondary sarcomas, which fortunately are rare.

Conclusions

The influence of local control on survival has important implications for treatment decisions in patients with breast cancer. The landmark EBCTCG Oxford meta-analysis clearly demonstrated for the first time the link between effective local therapy and long-term survival. This meta-analysis suggested a 4:1 ratio between absolute reductions in 5-year local recurrence and absolute reductions in 15-year mortality. The subgroup analyses of the Danish trials emphasizes that the Oxford overview 4:1 ratio is a simplification of how local control translates to a survival benefit. Outcomes are clearly influenced by the relative risk of local vs distant disease. These two competing risks can be further tempered by biologic subtype and the effectiveness of systemic therapy, both systemically and locally.

A multidisciplinary approach is vital to the continued improvements in overall survival. Clinicians must consider both the reduction of distant metastases and the degree of improvement in local control when making decisions regarding treatment modalities. The characterization of prognostic subgroups based on tumor characteristics can provide additional decision-making support for women diagnosed with breast cancer. As scientific investigation helps identify biologic subsets and new prognostic and predictive markers that help differentiate tumor response to therapy, the prospect of individualizing treatment plans for each individual patient increases. The ability to appropriately tailor local and systemic therapy to reduce rates of local recurrence is vital toward continuing the decline in breast cancer mortality.

Finally, radiation oncologists need to perform CT-based simulation to assess cardiac dose/volume. A number of techniques available to minimize cardiac dose both after BCS and mastectomy need to be employed to maximize long-term survival.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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