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Editorial |
From the Department of Surgery, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio; and Cancer Center, Aultman Health Foundation, Canton, Ohio.
The initial goal of neoadjuvant chemotherapy in breast cancer was to convert patients with inoperable disease to operable candidates. The rationale expanded to include patients with large, operable breast cancer in an effort to increase rates of breast-conserving surgery. Several randomized1–3 and nonrandomized trials4–7 have demonstrated that neoadjuvant chemotherapy significantly reduces mastectomy rates in this group of patients. Encouraged by these results, several investigators subsequently demonstrated that neoadjuvant chemotherapy can also reduce mastectomy rates in patients with locally advanced disease without significantly increasing local recurrence rates.8–11 These studies, however, included only a small number of patients with skin involvement, which makes this situation a relative contraindication to breast conservation, even after a good clinical response to neoadjuvant chemotherapy. The study by Shen et al.12 from M. D. Anderson Cancer Center in this issue of the Annals of Surgical Oncology suggests that, even in this group of patients with aggressive locally advanced disease, breast conservation is feasible with reasonably low local recurrence rates. Despite the small numbers included in this study, this report is useful in expanding the potential pool of patients with locally advanced breast cancer in whom a mastectomy can be avoided.
Several factors have contributed to the success of breast-conserving surgery following neoadjuvant chemotherapy in patients with locally advanced breast cancer. More active chemotherapy regimens (with the introduction of anthracycline and taxane) have significantly increased clinical and pathologic complete response rates and, thus, have made wide excisions with good cosmetic results possible in a substantial proportion of patients. Newer imaging modalities (e.g., breast magnetic resonance imaging [MRI]) can delineate more accurately than mammography the extent and growth patterns of primary breast tumors and the amount of residual disease following neoadjuvant chemotherapy.13–16 Perhaps, more importantly, MRI can identify several distinct patterns of tumor growth that have been associated with varying response rates17,18 and are predictive of the ability to perform breast-conserving surgery after neoadjuvant chemotherapy.19 The ability to insert radiopaque markers under mammographic or sonographic guidance at the site of the primary tumor has enhanced our ability to identify the exact tumor location in cases of complete clinical or radiologic response or the area of the previous tumor location in cases of pathologic complete response.20–22
Although the original clinical impetus for the use of neoadjuvant chemotherapy in operable and locally advanced breast cancer was to reduce the extent of surgery in the breast and avoid mastectomy, the advent of sentinel node biopsy has introduced another potential benefit with the use of neoadjuvant chemotherapy. Because neoadjuvant chemotherapy downstages axillary lymph nodes in a considerable proportion of patients (up to 40% with anthracycline and taxane-containing regimens),2,3,23,24 it was hypothesized that patients with involved nodes at diagnosis could be spared from an axillary dissection if, after neoadjuvant chemotherapy, sentinel node biopsy revealed negative sentinel node(s). Several single-institution and multicenter studies have examined the question of feasibility and accuracy of sentinel node biopsy following neoadjuvant chemotherapy.25 Although the evidence is much less definitive in this setting compared with performing the procedure before systemic therapy, data viewed collectively indicate that the performance characteristics of sentinel node biopsy are similar between the two approaches (identification rate of approximately 90% and the false—negative rate of approximately 11%).26–30 Adoption of sentinel node biopsy after neoadjuvant chemotherapy is likely to have a greater impact on patients with locally advanced breast cancer as opposed to those with operable disease because neoadjuvant chemotherapy and axillary nodal involvement are considerably more frequent in the former group.
Besides reducing the extent of surgery in the breast and axilla, neoadjuvant chemotherapy also has the potential to tailor the use of adjuvant loco-regional radiotherapy. Recent results in patients with operable breast cancer suggest that the pathologic response of the primary breast tumor and the pathologic status of axillary nodes after neoadjuvant chemotherapy are independent predictors of loco-regional failure. Thus, cohorts of patients at high or low risk for loco-regional failure can be identified in which the extent of loco-regional radiotherapy can be individualized.31 In patients with locally advanced disease, pathologic status of axillary nodes after neoadjuvant chemotherapy is also an independent predictor of loco-regional failure. In this group of patients, however, the rate of loco-regional failure, even in the low risk group, is substantial, and generally necessitates the use of radiotherapy.32
As we look to the future, neoadjuvant chemotherapy (possibly with the addition of targeted therapies) will continue to play an increasing role in influencing the loco-regional management of patients with breast cancer. Continuing development of more active regimens, further improvements in imaging modalities, and advances in molecular profiling undoubtedly will provide unique opportunities to test several provocative questions of loco-regional therapy in patients with operable and locally advanced breast cancer.
For the management of primary breast tumors, it is possible that the primacy of, or even the need for, open surgical resection could be questioned in the not too distant future, at least in selective subsets of patients. Although pathologic complete response rates with currently used regimens are in the range of 20% to 30%, newer strategies could push these rates considerably higher. In a small, randomized trial,33 which was presented recently in abstract form, pathologic complete response rates reached 65% with the addition of trastuzumab to an anthracycline and taxane-containing regimen in patients whose tumors overexpressed the HER-2 neu oncogene. Although these findings need to be confirmed in larger cohorts of patients, they hold significant promise that the pathologic complete response rates obtained with existing chemotherapy regimens can be substantially improved by adding novel targeted therapies in appropriately defined subsets of patients. Furthermore, previous studies, in which neoadjuvant chemotherapy was followed by breast radiation and then surgical resection, have already shown higher rates of pathologic complete response (>40%), delineating yet another strategy by which the primary breast tumor can be eradicated by nonsurgical means.34,35 On the other hand, in similar studies, in which breast irradiation was not followed by surgical resection, high rates of ipsilateral breast tumor recurrence were observed.4,36,37 Thus, if in future studies elimination of surgical resection were to be considered, either before or after breast radiation, patients at high likelihood for pathologic complete response need to be identified by molecular profiling and sensitive imaging studies and pathologic complete response needs to be confirmed by percutaneous biopsy of the tumor bed area. Newer percutaneous tumor ablation techniques (e.g., radiofrequency ablation or cryoablation)38 may also become a substitute for surgical excision, either before or after breast irradiation, in selected patients with complete clinical and radiologic response. Before widespread adoption of these tumor ablation techniques, their safety and efficacy need to be documented in prospective clinical trials.
Similar strategies need to be explored for the surgical management of the axilla. By using molecular profiling or sensitive imaging techniques, patients at high likelihood of having negative axillary nodes could be identified. For these patients, sentinel node biopsy alone could become the procedure of choice and even omission of axillary surgery could be considered. Although currently available imaging techniques (e.g., MRI, contrast-enhanced computed tomography scan, positron emission tomography scan, and sestamibi scan) have low sensitivity in predicting the subclinical involvement of axillary nodes,39 newer MRI approaches (e.g., use of ultrasmall superparamagnetic iron oxide [USPIO] enhancement) have shown promise in their ability to increase the sensitivity and specificity of MRI in detecting axillary nodal involvement.40 For those patients with a positive sentinel node after neoadjuvant chemotherapy, the most appropriate regional therapy strategy (surgery vs. radiotherapy) is currently under investigation.41,42
Finally, a clinical situation of unmet need relative to further increasing the rates of breast-conserving surgery involves patients who present with widespread intraductal carcinoma with or without an associated invasive breast tumor. Those patients are typically candidates for mastectomy because adequate surgical resection with acceptable cosmetic result cannot be achieved. The development of multiple new active targeted therapies (e.g., aromatase inhibitors, pure antiestrogens, EGFR/HER-2 neu inhibitors, COX-2 inhibitors, angiogenesis inhibitors) allows for an intriguing hypothesis to be tested in future studies (i.e., whether this intraductal neoplastic process could be reversed with neoadjuvant administration of some of these agents, either individually or in combination).43 Monitoring and documenting such reversal of the intraductal malignant process can be achieved by sensitive radiologic studies such as MRI,44 although mammography could also be helpful if response of the intraductal process to the neoadjuvant therapy correlates with a reduction in the extent of malignant microcalcification. Serial core biopsies of the areas in question would be the most definitive method to document a reversal in the malignant process as the patient has neoadjuvant therapy.
As part of the multidisciplinary team, surgeons should continue to lead the charge to minimize traditional surgical interventions in breast cancer by using appropriate neoadjuvant systemic therapy. Investigators from M. D. Anderson Cancer Center have played a significant role in this field over the past several years and should be applauded for their efforts. By asking and answering provocative questions, they have contributed significantly in advancing the state of the art in this field.
ACKNOWLEDGMENT
Investigators from MD Anderson Cancer Center have played a significant role in this field over the past several years and should be applauded for their efforts. By asking and answering provocative questions they have contributed significantly in advancing the state of the art in this field.
FOOTNOTES
Received August 2, 2004; accepted August 23, 2004.
Address correspondence to: Eleftherios P. Mamounas, MD, MPH, FACS, Cancer Center, Aultman Health Foundation, 2600 6th Street, Canton, OH 44710; Fax: 330-363-7367; E-mail: tmamounas{at}aultman.com.
REFERENCES
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