1. Management of the axilla in early breast cancer patients in the genomic era M. Oliveira, J. Cortés, M. Bellet, J. Balmaña, L. De Mattos-Arruda, P. Gómez, E. Muñoz, V. Ortega, J. Pérez, C. Saura, M. Vidal, I. T. Rubio & S. Di Cosimo Annals of Oncology 24: 1163–1170, 2013 R4 김승민 /prof 김시영

2. Introduction Management of the axilla in EBC patients has dramatically evolved recently, from more radical to increasingly conservative approaches EBC patients with a clinically positive axilla (cN+)  axillary lymph node dissection (ALND) EBC patients with a clinically negative axilla (cN0)  sentinel lymph node (SLN) biopsy and ALND only in the presence of a positive SLN. This obviates the complications related to ALND and provides adequate surgical staging and comparable locoregional control and survival.

3. Introduction ALND (SLN +) & contemporary adjuvant treatment (RT, CTx, Hx) is delivered has been questioned in recent years ongoing trials are testing whether node-positive patients can be spared chemotherapy ?  breast cancer biology for decision making regarding adjuvant systemic treatment we provide an overview of the current challenges that a more detailed knowledge of tumor biology has brought to EBC staging & treatment.

4. current perspectives on ALND in EBC Staging of the axilla is a comprehensive process that involves clinical examination, imaging and surgery. Table 1 summarizes the sensitivity and specificity of the imaging techniques used in clinical practice. Arguments in favor of performing ALND in cN0 EBC patients  complete axillary staging  likelihood of decreasing loco regional relapse  possibility of an accurate adjuvant systemic treatment planning, and improved survival rates. The probability of finding a positive SLN in cN0 EBC patients is 20%– 30%.

5. current perspectives on ALND in EBC Some characteristics of the primary tumor—lymphovascular invasion, tumor size, nuclear grade and tumor palpability—independently predict SLN involvement. In the presence of a positive SLN, the primary tumor size >2 cm, lymphovascular invasion, SLN extracapsular extension, SLN metastases >2 mm, presence of one or more positive SLNs, absence of non-involved SLN (of the total SLNs removed), the ratio of positive SLN >50%  independently predict the likelihood of non-SLN metastases

6. current perspectives on ALND in EBC Several models including most of these variables are available for clinical decision-making on performing ALND In the pre-SLN biopsy era, the EBC patients with cN0 and no axillary surgery presented axillary relapse rates of 15%–37%, which is reduced to <5% by radiotherapy. Patients undergoing ALND, in turn, have axillary recurrence rates around 1%. Of note, most of the studies reporting on axillary relapse are retrospective, and the impact of modern adjuvant systemic treatment on axillary recurrence of a non-surgically treated axilla is unknown.

7. current perspectives on ALND in EBC A key point when considering ALND in cN0 EBC patients is whether this procedure improves survival ? In favor of more extensive axillary dissection, data from SEER database, 72102 patients, single-primary breast lesion, 0-3 (+) breast nodes,  the number of removed nodes significantly affects the 10-year survival rate. In this study, the hazard ratio (HR), not significant in node-negative women aged 40–49 years, HR 0.920 in women aged 40–49 (95% CI 0.672–0.979) HR 0.906 in women aged 50–79 years(95% CI 0.763–0.938), ALND versus no ALND, recent meta-analysis, 2936 patient  an absolute survival benefit of 5.4% (95% CI 2.7–8) with ALND.

8. current perspectives on ALND in EBC Opposite conclusions regarding the impact of ALND on survival come from the NSABP B-04 study. 1079 cN0 women for radical mastectomy, total mastectomy + RTx or total mastectomy plus ALND (if the nodes became positive) 586 cN+ women to radical mastectomy or total mastectomy + RTx None of the patients received adjuvant systemic therapy. No significant differences were observed among the three groups of women with negative nodes or between the two groups of women with positive nodes with respect to DFS, relapse-free survival, distant- disease-free survival, or overall survival (OS)

9. current perspectives on ALND in EBC A more recent meta-analysis of four other studies failed to demonstrate a survival benefit for ALND in cN0 patients with earlier-stage breast tumors. Despite the small increase in axillary relapse in the absence of ALND, this rate was still extremely low in a context where adjuvant systemic therapy and breast radiotherapy are delivered to most of the patients. In summary, this survival advantage may no longer exist in the setting of earlier-stage cN0 breast cancer

10. current perspectives on ALND in EBC Early and late complications from ALND should also be considered. The early complications include skin erythema, seroma, wound infection, and inadvertent damage to neurovascular structures. The late complications include postoperative pain, limitations of shoulder movements, paresthesia, numbness of the upper arm, and lymphedema Moreover, ALND involves a longer hospital stay, which has cost implications. a key question is whether patients with a positive SLN must complete ALND or whether some patients (or eventually all) could avoid the potential morbidity of ALND without compromising outcomes.

11. omission of ALND if the SLN biopsy is positive (ACOSOG) Z0011 trial suggest that ALND may be omitted in selected patients with one or two positive SLNs. randomized 813 patients with clinical T1–2N0 tumors, BCS & SLN biopsy and had (H&E)-positive SLN  ALND versus no further axillary surgery Locoregional relapse not statistically different between the two groups (4.1% versus 2.8%). Compared with ALND, the use of SLN biopsy did not appear to result in statistically inferior survival (P = 0.008 for non-inferiority). because a SLN biopsy alone provides excellent locoregional control and survival rates comparable with ALND in patients (RTx, CTx)

12. omission of ALND if the SLN biopsy is positive isolated tumor cells (ITCs; <0.2 mm) micrometastases (tumor clusters 0.2–2 mm)  worse prognosis in patients undergoing ALND if no adjuvant systemic treatment is delivered. For instance, among 10111 patients with invasive breast cancer the relative risk of death in patients with micrometastases compared with patients with no metastases in the axillary lymph nodes after ALND was 1.32 in the whole population. When considering only patients who did not receive adjuvant systemic treatment, the relative risk of dying rose to 1.51.

13. omission of ALND if the SLN biopsy is positive The prognostic significance of isolated tumor cells or micrometastasis in the SLN is currently unclear. The proportion of patients who omit ALND in the presence of micrometastases in SLN is increasing, especially among older patients with small/low-grade tumors with no lymphovascular invasion. Andersson et al reported a decreased event-free survival in the presence of micrometastases in the SLN, with an HR of 1.71 (P = 0.032), but no impact on OS (HR 1.48, P = 0.258). Another study, 790 patients found that ITCs or micrometastases did not confer a worse 8-year DFS or OS when compared with SNL biopsy- negative patients.

14. omission of ALND if the SLN biopsy is positive the Dutch MIRROR study node-negative disease,not received systemic adjuvant Tx(Group A), ITCs or micrometastases,not received systemic adjuvant Tx (Group B), ITCs or micrometastases,received such treatment (Group C) 63% hormonal therapy only, 6% chemotherapy only, and 31% both. In this study, the patients in Group B had a reduced 5-year rate of DFS when compared with those in Group A (76.5% versus 85.7%). In patients with micrometastases or ITCs, the 5-year rate of DFS was significantly improved with the use of adjuvant systemic treatment (86.2% versus 76.5%).

15. omission of ALND if the SLN biopsy is positive Data from three observational prospective studies carried out in recent years are reported in Table 2. The ACOSOG Z0010, 3945 patients with a SLN assessed (H&E or IHC)  determine the clinical significance of finding micrometastases and/or ITCs. In this study, occult metastases were found by immunohistochemistry (IHC) in 8.9% of the patients the 5-year survival rates were not different between patients who were H&E-negative/IHC-negative & those who were H&E negative/ IHC- positive (95.8% versus 95.1%)

16. omission of ALND if the SLN biopsy is positive The NSABP B-32 study randomized 5611 patients to receive SLN biopsy with immediate ALND or SLN biopsy alone In this study, occult metastases were found by IHC in 15.9% of 3887 H&E-negative patients. OS, DFS, and distant DFS (DDFS) were significantly worse for IHC- positive patients than for IHC-negative patients, the absolute difference in 5-year OS rates was only 1.2% (94.6% versus 95.8%, P = 0.03). authors concluded that the magnitude of difference in the outcome at 5years was small

17. omission of ALND if the SLN biopsy is positive the IBCSG 23–01 trial, patients with minimal SLN involvement one or more micrometastatic (≤2 mm) SLNs + tumors ≤5 cm  ALND versus no further axillary surgery. the 5-year DFS rates in the ALND and no ALND groups were 87.3% and 88.4%, non-inferiority. The 5-year OS rates were also similar between both the groups (97.6% and 98%, respectively) The authors concluded that patients with micrometastases in the SLN could be spared ALND without compromising longterm outcomes

18. omission of ALND if the SLN biopsy is positive In summary, the presence of micrometastases in the SLN does not affect survival outcomes in patients receiving contemporary adjuvant treatment. Most of the patients enrolled in these trials had ALND (hence, a more accurate axillary staging) and were hormone receptor positive. Of note, it is currently unknown whether the prognostic meaning of micrometastases or ITCs in SLN varies according to each breast cancer subtype

19. integrating tumor biology in axillary management In 2000, using an innovative gene expression analysis, Charles Perou et al. characterized variation in gene expression patterns The tumors could be classified into four major subtypes distinguished by pervasive differences in their gene expression patterns. basal-like, HER2-enriched, normal-like and luminal This and other experiments confirmed that breast cancer is not a single disease with variable morphological features the intrinsic biological behavior of which may influence natural history and, consequently, clinical management

20. tools for clinical outcome prediction Several gene signatures were subsequently developed to provide better predictions of clinical outcome OncotypeDX® is a 21-gene reverse transcription polymerase chain reaction assay that includes ER, HER2, ER-regulated transcripts, and several proliferation-related genes. By combining the expression levels of these genes, a quantitative recurrence score (RS) is calculated. (low-, intermediate- and high-risk) 10-year recurrence probability in women with ER-positive, node-negative breast cancer treated with tamoxifen alone NSABP B-14 trial. The greatest benefit from tamoxifen was observed in women with low and intermediate RS, with minimal benefits in women with high RS.

21. tools for clinical outcome prediction In ER-positive, node-negative women randomly assigned in the NSABP B-20 trial tamoxifen alone or CMF + tamoxifen, a substantial benefit in the reduction of distant recurrence from CMF in high-RS tumors, no benefit in low-RS tumors, and an uncertain benefit in intermediate-RS tumors RS results may have implications in decisions on locoregional therapy for patients with cN0 Er positive breast cancer. increasing RS has also been associated with the likelihood of achieving pathological complete response (pCR) after neoadjuvant chemotherapy,

22. tools for clinical outcome prediction Mammaprint® is the first FDA-cleared breast cancer recurrence assay. a gene signature was developed from a series of 78 npatients with node- negative, stage I–II breast cancer who had received no adjuvant systemic therapy. prognostic score that categorizes patients under ‘good’ and ‘poor’ risk groups. gene-expression profile was a more powerful predictor of the outcome of disease in young patients with breast cancer than the standard systems based on the clinical and histological criteria.

23. outcome prediction in node-positive disease Both OncotypeDX® and Mammaprint® seem to maintain their ability to predict recurrence in patients with node-positive disease. up to 25–30% of node-positive patients remain disease-free even if they do not receive adjuvant systemic therapy. these modern molecular tools could assist clinicians in identifying node- positive patients who could be spared chemotherapy without compromising long-term outcomes. phase 3 SWOG- 881 trial, a low RS can identify a population of node- positive women, not benefit from anthracycline-based chemotherapy. Similarly, Mammaprint® was significantly superior to the traditional prognostic factors in predicting breast cancer-specific survival..

24. ongoing validation trials Prospective trials, value of both OncotypeDX® and Mammaprint® in predicting the risk of recurrence in a set of patients whose clinical decisions about receiving adjuvant CTx SWOG S1007 (RxPONDER trial) The MINDACT trial, tests the ability of Mammaprint identification of patients with a low molecular risk of relapse, despite the number of positive axillary lymphnodes, is a subject of intense investigation. It is possible that women with node-positive disease can be spared chemotherapy in the future deciding whether to carry out an ALND in these patients ?

25. Conclusions The main goal of EBC management is delivering each patient tailored treatment. Along with surgical efforts aimed at sparing patients with low axillary tumor burden from undergoing ALND, medical oncologists pursue the accurate identification of EBC patients who can be spared chemotherapy. concept of surgical staging and nodal status as a prognostic factor should be replaced by an integrative biological and anatomical approach in EBC patients’ management. In this model, there may be certain patients for whom ALND is not necessary to cure cancer

26. Conclusions Conversely, negative SLN patients at a high risk of recurrence are candidates for adjuvant chemotherapy regardless of the outcome of ALND. breast cancer oncologists, either surgeons, radiation therapists, or medical oncologists, should focus their efforts on providing treatment tailored to each patient’s needs,.