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Long-Term Follow-Up Study of a Prospective Multicenter Sentinel Node Trial: Molecular Detection of Breast Cancer Sentinel Node Metastases
Long-Term Follow-Up Study of a Prospective Multicenter Sentinel Node Trial: Molecular Detection of Breast Cancer Sentinel Node Metastases Verbanac KM, for the ECU/AAMC Sentinel Node Study Group (The Brody School of Medicine at East Carolina Univ, Greenville, NC; et al) Ann Surg Oncol 17:S368-S377, 2010
Background.dThis prospective multicenter sentinel lymph node (SLN) trial investigated whether molecular analysis would improve the detection of SLN metastases and their prognostic value. We report mammaglobin quantitative real-time polymerase chain reaction (qRT-PCR) results and clinical outcome for 547 patients (mean follow-up 7 years). Methods.dBreast cancer patients (excluding stage IV disease or palpable nodes) were enrolled from 1996 to 2005 at 16 institutional review boardapproved sites. Alternate 2-mm serial sections of each SLN were examined by hematoxylin and eosin staining with or without immunohistochemistry at multiple levels or blinded and assayed by Taqman qRT-PCR according to previously established thresholds. Results.dMammaglobin remains a highly specific (99%), sensitive (97% primary tumor; 82% N1 SLN) marker for breast cancer. Mammaglobin SLN expression was associated with other prognostic factors, was detected in most patients with distant recurrence (48 of 79; 61%), and was associated with decreased recurrence-free survival (log rank P < 0.0001). Molecular analysis upstaged 13% (52 of 394) nodenegative (N0) patients who exhibited a significantly lower distant recurrencefree survival compared to nodenegative, PCR-negative patients (80 vs. 91%; P < 0.04). N0 patients with PCRpositive SLN were 3.4 times more likely
392
to experience relapse than PCR-negative patients (odds ratio 3.4; 95% confidence interval 1.6e7.1; P ¼ 0.001). However, molecular staging failed to predict most of the N0 patient recurrences (25 of 34) and was not a statistically significant independent predictor of distant recurrence. Conclusions.dTo our knowledge, these data are the first to prospectively compare PCR detection of SLN metastases with long-term outcome in breast cancer patients. Molecular staging of SLN detected clinically significant disease missed by standard pathology. Further refinement and optimization of molecular staging is indicated to improve clinical utility. Over the last 15 years, the use of SLN biopsy in the management of breast cancer has led to greater accuracy in detecting small-volume disease in regional nodes. The ability to focus on a handful of SLNs and the application of more complex methodologies to assess these SLNs have resulted in the progressive upstaging of cases that would historically have been considered N0. It is, therefore, not surprising to find, as Verbanac and colleagues report, that PCR analysis of SLNs upstaged 13% of N0 breast cancer cases. But how should these data be interpreted, and how should or will they affect disease management? The authors are to be commended for conducting this large multicenter trial and for their thoroughness in establishing parameters for performing and interpreting the results of the PCR assay. As they clearly show, women who had PCR-positive nodes had poorer outcomes than women with PCR-negative nodes. However, as they also point out, most women with PCRpositive nodes did not relapse; conversely, many women who did relapse did not have PCR-positive nodes; conversely, many women who
Breast Diseases: A Year BookÒ Quarterly Vol 22 No 4 2012
did relapse had PCR-negative nodes. This finding suggests that the biological behavior of tumors cannot be fully predicted, even as we develop increasingly more sensitive ways to identify disease in the regional nodes. In the years since this study was initiated, additional areas of investigation, such as circulating tumor cells and tumor cells disseminated to the bone marrow, have come to the fore as sites of occult disease that predict tumor behavior and patient outcomes, even among women with N0 disease.1-5 Importantly, these areas of occult disease often show no correlation to nodal status. Therefore, it appears that understanding hematogenous disease spread is as important as understanding lymphatic disease spread and that often these are independent processes. From this perspective, then, it is not surprising to see that women with PCR-negative nodes relapsed with distant disease and that, clearly, the additional PCR-based staging of these cases was of no clinical benefit. But what of the women who had PCR-positive nodes and who remain free of disease? It is of interest that the authors report that receipt of adjuvant chemotherapy and hormone therapy was similar between the PCR-positive and PCR-negative patient groups within the pathology-negative subset. There was also no association between PCR status and systemic treatment received among women who had disease recurrence. Thus, the analysis of survival outcomes does not appear to have been confounded by treatment biases. Furthermore, while PCR-positive nodal status was associated with worse outcome on univariate analysis, it did not reach significance in multivariate modeling. Thus, while it is possible that longer follow-up may be required to identify relapses in women with very limited nodal involvement, or that a certain subset may be identified in whom PCR
positivity is of greater prognostic value, for most breast cancer patients, the test appears to be overly sensitive. Overall, these data from Verbanac and colleagues’ study suggest that the impact and utility of identifying the PCR status of SLNs in breast cancer is very limited. Over the last decade, breast cancer therapy has moved toward a greater understanding of tumor biology and the development of personalized, targeted treatment strategies based on underlying pathway aberrations. In this new paradigm, it seems likely that we will continue to shift away from focusing on the detection of very small amounts of disease in
the axilla as a predictor of tumor behavior.
Accuracy of sentinel lymph node biopsy after neo-adjuvant chemotherapy in patients with locally advanced breast cancer and clinically positive axillary nodes
and complete axillary lymph node dissection (ALND). The status of the sentinel lymph node (SLN) was compared to that of the axilla. Results.dAt least one SLN was identified in 60 of the 64 patients (93.8%). Among those 60 patients, 37 (61.7%) had one or more positive SLN(s) and 23 (38.3%) did not. Two of the patients with negative SLN(s) presented metastases in other nonsentinel nodes. SLNB thus had a falsenegative rate, a negative predictive value and an overall accuracy of 5.1%, 91.3% and 96.7%, respectively. All these values were similar to those we reported for SLNB in the settings of early-stage breast cancer. Conclusion.dSLNB after NAC is safe and feasible in patients with locally advanced breast cancer and clinically positive nodes, and accurately predicts the status of the axilla.
Canavese G, Dozin B, Vecchio C, et al (Natl Cancer Res Inst, Genova, Italy; et al) Eur J Surg Oncol 37:688-694, 2011
Background.dFeasibility and accuracy of sentinel node biopsy (SLNB) after the delivery of neo-adjuvant chemotherapy (NAC) is controversial. We here report our experience in NACtreated patients with locally advanced breast cancer and clinically positive axillary nodes, and compare it with the results from our previous randomized trial assessing SLNB in early-stage breast cancer patients. Patients and Methods.dSixtyfour consecutive patients with large infiltrating tumor and clinically positive axillary nodes received NAC and subsequent lymphatic mapping, SLNB
I. Bedrosian, MD
References 1. Braun S, Pantel K, Mu¨ller P, et al. Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med. 2000;342:525-533. 2. Braun S, Vogl FD, Naume B, et al. A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med. 2005;353:793-802.
cytokeratin-19 mRNA positive circulating tumor cells according to estrogen receptor and HER2 status in early-stage breast cancer. J Clin Oncol. 2007;25:5194-5202. 4. Pierga JY, Bidard FC, Mathiot C, et al. Circulating tumor cell detection predicts early metastatic relapse after neoadjuvant chemotherapy in large operable and locally advanced breast cancer in a phase II randomized trial. Clin Cancer Res. 2008;14:7004-7010. 5. Bidard FC, Mathiot C, Delaloge S, et al. Single circulating tumor cell detection and overall survival in nonmetastatic breast cancer. Ann Oncol. 2010;21:729-733.
3. Ignatiadis M, Xenidis N, Perraki M, et al. Different prognostic value of
Modern NAC regimens successfully eradicate disease in 40% of patients who present with axillary adenopathy at
the time of diagnosis.1 Accordingly, a major potential advantage of using NAC rather than adjuvant systemic treatments in this setting is to avoid the morbidity associated with ALND in nearly half of the patients. However, a highly sensitive method of determining which patients have persistent axillary disease is needed before forgoing ALND. To address this, SLNB is intuitively the best approach, and this study by Canavese and colleagues and others like it provide valuable insights into how commonly SLNB inaccurately predicts the status of the axilla. It is conceivable that disease response varies in different lymph nodes such that disease could be completely eradicated in an SLN but not in other axillary lymph nodes. This may increase the falsenegative rate compared with that reported for patients not treated with NAC. However, if SLNB is a valid approach, it is exciting to potentially avoid ALND in 40% of patients who present with clinically positive axillary disease.
Breast Diseases: A Year BookÒ Quarterly Vol 22 No 4 2012
393
Background.dThis prospective multicenter sentinel lymph node (SLN) trial investigated whether molecular analysis would improve the detection of SLN metastases and their prognostic value. We report mammaglobin quantitative real-time polymerase chain reaction (qRT-PCR) results and clinical outcome for 547 patients (mean follow-up 7 years). Methods.dBreast cancer patients (excluding stage IV disease or palpable nodes) were enrolled from 1996 to 2005 at 16 institutional review boardapproved sites. Alternate 2-mm serial sections of each SLN were examined by hematoxylin and eosin staining with or without immunohistochemistry at multiple levels or blinded and assayed by Taqman qRT-PCR according to previously established thresholds. Results.dMammaglobin remains a highly specific (99%), sensitive (97% primary tumor; 82% N1 SLN) marker for breast cancer. Mammaglobin SLN expression was associated with other prognostic factors, was detected in most patients with distant recurrence (48 of 79; 61%), and was associated with decreased recurrence-free survival (log rank P < 0.0001). Molecular analysis upstaged 13% (52 of 394) nodenegative (N0) patients who exhibited a significantly lower distant recurrencefree survival compared to nodenegative, PCR-negative patients (80 vs. 91%; P < 0.04). N0 patients with PCRpositive SLN were 3.4 times more likely
392
to experience relapse than PCR-negative patients (odds ratio 3.4; 95% confidence interval 1.6e7.1; P ¼ 0.001). However, molecular staging failed to predict most of the N0 patient recurrences (25 of 34) and was not a statistically significant independent predictor of distant recurrence. Conclusions.dTo our knowledge, these data are the first to prospectively compare PCR detection of SLN metastases with long-term outcome in breast cancer patients. Molecular staging of SLN detected clinically significant disease missed by standard pathology. Further refinement and optimization of molecular staging is indicated to improve clinical utility. Over the last 15 years, the use of SLN biopsy in the management of breast cancer has led to greater accuracy in detecting small-volume disease in regional nodes. The ability to focus on a handful of SLNs and the application of more complex methodologies to assess these SLNs have resulted in the progressive upstaging of cases that would historically have been considered N0. It is, therefore, not surprising to find, as Verbanac and colleagues report, that PCR analysis of SLNs upstaged 13% of N0 breast cancer cases. But how should these data be interpreted, and how should or will they affect disease management? The authors are to be commended for conducting this large multicenter trial and for their thoroughness in establishing parameters for performing and interpreting the results of the PCR assay. As they clearly show, women who had PCR-positive nodes had poorer outcomes than women with PCR-negative nodes. However, as they also point out, most women with PCRpositive nodes did not relapse; conversely, many women who did relapse did not have PCR-positive nodes; conversely, many women who
Breast Diseases: A Year BookÒ Quarterly Vol 22 No 4 2012
did relapse had PCR-negative nodes. This finding suggests that the biological behavior of tumors cannot be fully predicted, even as we develop increasingly more sensitive ways to identify disease in the regional nodes. In the years since this study was initiated, additional areas of investigation, such as circulating tumor cells and tumor cells disseminated to the bone marrow, have come to the fore as sites of occult disease that predict tumor behavior and patient outcomes, even among women with N0 disease.1-5 Importantly, these areas of occult disease often show no correlation to nodal status. Therefore, it appears that understanding hematogenous disease spread is as important as understanding lymphatic disease spread and that often these are independent processes. From this perspective, then, it is not surprising to see that women with PCR-negative nodes relapsed with distant disease and that, clearly, the additional PCR-based staging of these cases was of no clinical benefit. But what of the women who had PCR-positive nodes and who remain free of disease? It is of interest that the authors report that receipt of adjuvant chemotherapy and hormone therapy was similar between the PCR-positive and PCR-negative patient groups within the pathology-negative subset. There was also no association between PCR status and systemic treatment received among women who had disease recurrence. Thus, the analysis of survival outcomes does not appear to have been confounded by treatment biases. Furthermore, while PCR-positive nodal status was associated with worse outcome on univariate analysis, it did not reach significance in multivariate modeling. Thus, while it is possible that longer follow-up may be required to identify relapses in women with very limited nodal involvement, or that a certain subset may be identified in whom PCR
positivity is of greater prognostic value, for most breast cancer patients, the test appears to be overly sensitive. Overall, these data from Verbanac and colleagues’ study suggest that the impact and utility of identifying the PCR status of SLNs in breast cancer is very limited. Over the last decade, breast cancer therapy has moved toward a greater understanding of tumor biology and the development of personalized, targeted treatment strategies based on underlying pathway aberrations. In this new paradigm, it seems likely that we will continue to shift away from focusing on the detection of very small amounts of disease in
the axilla as a predictor of tumor behavior.
Accuracy of sentinel lymph node biopsy after neo-adjuvant chemotherapy in patients with locally advanced breast cancer and clinically positive axillary nodes
and complete axillary lymph node dissection (ALND). The status of the sentinel lymph node (SLN) was compared to that of the axilla. Results.dAt least one SLN was identified in 60 of the 64 patients (93.8%). Among those 60 patients, 37 (61.7%) had one or more positive SLN(s) and 23 (38.3%) did not. Two of the patients with negative SLN(s) presented metastases in other nonsentinel nodes. SLNB thus had a falsenegative rate, a negative predictive value and an overall accuracy of 5.1%, 91.3% and 96.7%, respectively. All these values were similar to those we reported for SLNB in the settings of early-stage breast cancer. Conclusion.dSLNB after NAC is safe and feasible in patients with locally advanced breast cancer and clinically positive nodes, and accurately predicts the status of the axilla.
Canavese G, Dozin B, Vecchio C, et al (Natl Cancer Res Inst, Genova, Italy; et al) Eur J Surg Oncol 37:688-694, 2011
Background.dFeasibility and accuracy of sentinel node biopsy (SLNB) after the delivery of neo-adjuvant chemotherapy (NAC) is controversial. We here report our experience in NACtreated patients with locally advanced breast cancer and clinically positive axillary nodes, and compare it with the results from our previous randomized trial assessing SLNB in early-stage breast cancer patients. Patients and Methods.dSixtyfour consecutive patients with large infiltrating tumor and clinically positive axillary nodes received NAC and subsequent lymphatic mapping, SLNB
I. Bedrosian, MD
References 1. Braun S, Pantel K, Mu¨ller P, et al. Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med. 2000;342:525-533. 2. Braun S, Vogl FD, Naume B, et al. A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med. 2005;353:793-802.
cytokeratin-19 mRNA positive circulating tumor cells according to estrogen receptor and HER2 status in early-stage breast cancer. J Clin Oncol. 2007;25:5194-5202. 4. Pierga JY, Bidard FC, Mathiot C, et al. Circulating tumor cell detection predicts early metastatic relapse after neoadjuvant chemotherapy in large operable and locally advanced breast cancer in a phase II randomized trial. Clin Cancer Res. 2008;14:7004-7010. 5. Bidard FC, Mathiot C, Delaloge S, et al. Single circulating tumor cell detection and overall survival in nonmetastatic breast cancer. Ann Oncol. 2010;21:729-733.
3. Ignatiadis M, Xenidis N, Perraki M, et al. Different prognostic value of
Modern NAC regimens successfully eradicate disease in 40% of patients who present with axillary adenopathy at
the time of diagnosis.1 Accordingly, a major potential advantage of using NAC rather than adjuvant systemic treatments in this setting is to avoid the morbidity associated with ALND in nearly half of the patients. However, a highly sensitive method of determining which patients have persistent axillary disease is needed before forgoing ALND. To address this, SLNB is intuitively the best approach, and this study by Canavese and colleagues and others like it provide valuable insights into how commonly SLNB inaccurately predicts the status of the axilla. It is conceivable that disease response varies in different lymph nodes such that disease could be completely eradicated in an SLN but not in other axillary lymph nodes. This may increase the falsenegative rate compared with that reported for patients not treated with NAC. However, if SLNB is a valid approach, it is exciting to potentially avoid ALND in 40% of patients who present with clinically positive axillary disease.
Breast Diseases: A Year BookÒ Quarterly Vol 22 No 4 2012
393