1. THE AXILLARY SWAMP INNOVATIVE TREATMENTS IN CANCER MEDICINE
ROME MAY
Isabel T. Rubio
Breast Surgical Unit,
Breast Cancer Center
Hospital Universitario Vall d´Hebron
Barcelona, Spain

2. 19th century
(an area of) very wet, soft land or it can be a situation fraught with difficulties and imponderables and along the history of breast cancer we have been struggling to know more about the role of lymph nodes that

3. Halstedian Era Halsted proved beyond any doubts that
76 patients treated with radical mastectomy
40 had survived > 3 years
36 had died within 3 years
The halstedian theory was based on the asume stepwise progresion of cancer cells from the local primary to the regional nodes acting as filters and only later to systemic therapy but the results were not as expected as many women still die from the disease, even though….
Halsted proved beyond any doubts that
meticulous surgeries were technically
possibly in breast cancer

4. Controversy
Statistical relationship between lymph node metastases and survival
Lymph node resections are related to survival
The meaning of micrometastasis and ITC
In most cancers
With or without lymph node metastases

5. “ Lymph node metastasis are predictors,
Fisherian theory
“ Lymph node metastasis are predictors,
not governors, of overall survival
since they do not control survival”
Blake Cady, Arch Surg 1984

6. The believe that Removing more negative nodes is the result of a Will Rogers effect on stage migration that occurs on more extensive tissue removal
one of the most important biases limiting the use of historical controls groups in experimental treatment trialsIf you harvest 20 nodes rather than 10 nodes you probably end up finding an unexpected positive node or mode, an example of stage shifting

7. Axillary Lymph Node Dissection
Goals
- Survival Advantage
- Accurate Staging
- Regional Control

8. Regional Treatment and Survival
NSABP B04
Regional Treatment and Survival

9. Survival Advantage with Axillary Dissection
Orr: Ann Surg Onc 1999
5.4% average survival advantage in axillary dissection group
Before screening mammography
Before development of effective systemic therapies
Before the introduction of margin control
Now, if we knew for sure that we could increase the survival of patients by an average of 5% or so with axillary therapy, then many would in fact agree that this should be recommended. Is there really a survival advantage? Which are the patients who will have a survival advantage? The 15 year of the Institut Curie shows no differences in survival, nor the 25 year follow up on NSABP

10. Veronesi U et al. Eur J Cancer 1999
The involvement of internal mammary was predictor of poor prognosis but there was no survival benefit from resecting those nodes
Veronesi U et al. Eur J Cancer 1999

11. Local Control Survival
Sabemos desde hace unos años que el control local y la supervivencia están relacionados y esto ha sido un cambio importante en el cáncer de mama. Pero hay un mensaje importante y es que hay que reducir la recidiva local en + 10% para obterenr beneficios en la supervivencia
EBCTCG. Lancet 2005

13. Sentinel Lymph Node Biopsy Works
Trial
N Patients
SLN
SLN-FN
Accuracy
EIO
532
99% 9%
97%
B-32
5611
10%
ALMANAC
836
96% 7%
98%
GIVOM
749
95%
17%
SNAC
1088
94% 5%

14. RANDOMIZED STUDIES

15. Unfavourable events
(Follow up 78 month )
EVENT
ALND SLN
Risk ratio (95%CI)
Breast cancer related events
Axillary metastases
Supraclavicular metastases
Tumour reappearanc/breast
Distant metastases
Total 2 3 13 18 1 4 11 16
1,26 (0,8-5,65)
0,8 (0,36-1,79)
0,84 (0,43-1,6)
Contralateral and other primary tumour
Contralateral breast cancer
Other primary tumour 6 12 36 5 27
0,79 ( 0,24-2,59)
0,47 (0,18-1,27)
0,71(0,43-1,18)
Deaths
Deaths from breast cancer
Deaths from other causes
Deaths of unknown cause
5 year overall
survival
96,4%
98,4%
1,44(0,24-8,63)
0,19 (0,02-1,65)
0,24(0,03-2,15)
0,44(0,15-1,26)

16. False negative = Axillary recurrence
Will SLN False Negative Rates Predict Nodal Recurrence Rates?
False negative = Axillary recurrence
SLN - /no ALND N
Axillary Recurrence
F/U
years
48 STUDIES
14.959
0.3%
> 3
NSABP B-32
2011
0.7% 8
SLN +/no ALND (6 studies)
583
0.5% 3
Most of the axillary recurrences appear between 18 and 36 months after surgery
Van der Ploeg et al. EJSO 2008
Krag DN et al. Lancet Oncology 2010

17. The greatest accomplishment of the SLN is to achieve the goal of avoiding removal of regional and nodal lymphatic basins that do not harbour metastastic disease
A decided break in the surgical tradictional conception of lymph nodes as effective filters blocking dissemination of cancer cells.

18. Rationale to Avoid ALND in SLN+ Patients
1. Impact on Lymphedema
2. SLN is Often the Only + LN
3. Adjuvant Therapy May Treat Subclinical Nodal Metastases
4. Most Data Indicate the ALND Does Not Improve Survival
5. ALND is for Staging

19. Bilomoria KY et.al. JCO 2009;27:2946-53
SLN + and no ALND
SLN+ and
no ALND %
Bilomoria KY et.al. JCO 2009;27:

20. Outcome +/- ALND Axillary local recurrence 5 yr relative survival
SLN micrometastases (<2 mm)
SLN only
(n=802)
0.4%
99%
SLN/ALND
(n=2357)
0.2%
98%
SLN macrometastases (>2 mm)
(n=5596)
1.0%
90%
SLN/ALND (n=22591)
1.1%
89%
Bilomoria KY et.al. JCO 2009

21. Management of the axilla when the SLN is positive

22. ACOSOG Z0011 ALND n = 420 SN n = 436 Local 15 (3.6%) 8 (1.8%) Regional
2 (0.5%)
4 (0.9%)
Total
17 (4.1%)
12 (2.8%)
p = 0.11
ACOSOG Z0011
ALND
n = 420 SN
n = 436
Local
19 (5.6%)
12 (3.8%)
Regional
2 (0.5%)
5 (1.5%)
Total
21 (6.2%)
17 (5.3%)
p = 0.36
Giuliano A, Ann Surg 2010;252:426

23. Mastectomy and +SLN Mastectomy w/o XRT or ALND (n=58)
Mastectomy (n=210) BCS (n=325)
LR 1.7% %
RR 1.2 (2.5%) % (1.5%)
Milgrom S. Ann Surg Oncol 2012
Mastectomy w/o XRT or ALND (n=58)
Fitzsullivan. Ann Surg Oncol 2017
without any axillary-specific treatment
Entre parétesis si se excluyen pN0(ITC

24. Removal of Positive Nodes
Lymph nodes metastases may or may not precede the distant metastasis
Presence of positive nodes is a predictor
Small volume of tumor burden in the axilla can be taken care of with systemic therapy
In the abscence of extensive axillary disease , removing positive nodes do not improve survival or increase locoregional control
Rather than an instigator of distant disease

25. Controversy
Statistical relationship between lymph node metastases and survival
Lymph node resections are related to survival
The meaning of micrometastasis and ITC
In most cancers
With or without lymph node metastases

26. Z0010 trial Survival by staining method
H&E
negative
(3945/5184)
positive
(1239/5184)
IHC
(3595)
(350)
5 year survival
(95% CI)
95.6%
( )
92.8%
( )
p=0.0002
95.8%
( )
95.1%
( )
p=0.53
Cote R et.al. ASCO 2010

27. Important issues already proven
1. Sentinel Lymph Node Biopsy Works 2. Improvements in systemic therapy have increased rates of pCR
Let´s start by mentioning that there are two issues already proven:
Improvements in systemic therapy have increased rates of pCR in the breast and in the axilla and it is time for us as surgeons to reevalute the local treatment in our patients

28. PROGNOSIS Cortazar P et al. Lancet 2014
Patients with no invasive tumor in the breast and the axilla p complete response that correlates best with long-term outcome,
The association between pathological complete response and long-term outcomes was strongest in patients with triple-negative breast
cancer (EFS: HR 0.24, 95% CI 0.18–0.33; OS: 0.16, 0.11–0.25) and in those with HER2-positive, hormone-receptornegative
tumours who received trastuzumab (EFS: 0.15, 0.09–0.27; OS: 0.08, 0.03, 0.22). Attaining pCR reduced the risk of death by 92% in cancers that were HER2 positive and hormone receptor–negative cancers and by 84% in (TNBCs).
Cortazar P et al. Lancet 2014

29. pCR rates vary by subtype
pCR rates vary depending on biologic subtype and therapy used
TNBC has higher pCR rates that HR+ disease
- 22% vs 11% in a study of patients
Her2 3+
- Rates up to 65% in pactients with Trastuzumab
- Rates higher in dual blockage
Sstudies further demonstrate that in subgroups considered to have slowly proliferating tumors, pCR is not associated with prognosis, whereas in subgroups with highly proliferating tumors, pCR increases in this subgroups up to 65%.
And how all this achievemt has impact on the surgical management?
Baselga . Lancet 2012
Gianni, Lancet Oncology 2012
Buzdar, JCO 2012

30. Can axillary node dissection be spared in patients after neoadjuvant treatments ?

31. Conversion of Axillary Metastases: FNA Positive to Pathologic Negative
109
patients
Pathologic
NEGATIVE
81 patients
Trastuzumab
+ A or T
HER2+
74%
Median # LNs Removed = 19
CANCER, 2010

32. Mamtani A. Ann Surg Oncol 2016
cT4 or cN2/N3 ineligible para SLN regardless of response
48% no ALND
Mamtani A. Ann Surg Oncol 2016

33. # patients with residual nodal disease 310 83 226 619
ACOSOG Z1071
FN SNAC
SENTINA
TOTAL STUDIES
N PATIENTS
756
153
592
1501
# patients with residual nodal disease
310 83
226
619
FNR with single SLN
31.5%
17/54
18.2%
4/22
24.3%
17/70
26%
36/146
FNR if >2 SLNs
12.6%
39/310
4.9%
3/61
9.6%
15/156
10.8%
57/527
FNR with dual tracer
27/251
5.2%
3/58
8.6%
6/70
9.5%
36/379
FNR inclusion of N0(i+)
8.7%
27/311
8.4%
7/83 -
34/394
, and further studies are necessary to help determine optimal axillary management.

34. Targeted Axillary Dissection (TAD)
1-5 Days Before Surgery
Day of Surgery
Breast Imaging
I125 seed placed in marked node
Node containing I125 seed selectively removed
I125 Seed
I125 Seed
Clip
The localize the clipped node, patients go to breast imaging 1-5 days before surgery. Similar to our approach for localizing breast tumors with I125 seeds, the radiologist places an I125 seed in the clipped node under US guidance. If SLN is planned, they either go to Nuclear Medicine for radioisotope injection the day before surgery or the surgeon injects the isotope in the OR. During their axillary surgery, the surgeon uses a neoprobe to identify the node containing the I-125 seed and clip. The SLNs are also removed. At this time, patients also undergo completion ALND.
Clip
SLNs removed
Remaining axillary nodes removed
Nuclear Medicine
Radioisotope injection for SLND
Courtesy Dr. Kuerer
Caudle et al. JAMA-Surg (2):

35. Diaz-Botero, S et al. Ann Surg Oncol 2016

36. Residual Disease After Neoadjuvant Treatment
Diaz-Botero, S et al. Ann Surg Oncol 2016

37. IMPORTANT POINTS TO CONSIDER
Refine the SLN technique after NACT
Improving SLN IR and reducing the chance of false negativity:
- Marking the + nodes - Dual mapping techniques - Resection of >2 SLN when possible - Following proper pathological evaluation - Broadening the definition of SLN positivity
to include micrometastases and isolated tumor cells Encouraging patients and junior doctors to enroll patients in future research programs

38. Follow up of patients with cN0 or cN1-2 before NAC
The European Institute of Oncology group reported that SLN among 147 patients initially node positive who converted to node negative after NACT had a 5 year axillary recurrence rate of only 0.7%
Patients with N1 disease who had a pCR, SN negativity was a significant predictor of good outcome, suggesting that SN status accurately reflect axillary status.
Galimberti V et al. EJSO 2016

39. Regional Failure Rates in other trials:
After mastectomy alone, fewer than 50% of N+ patients developed axillary first failure.
Conventional radiation tangents treat approx. 80% of Level 1, 50% Level 2 + 3
Adjuvant systemic rx reduces LRR by > 50%
NSABP B04: RM 40% N+, TM: 18.5% delayed ALND
NSABP B13: No Rx 13.4%, CTX 2.6%
NSABP B14: Placebo 14.7%, Tam 4.3%
Fisher B, NEJM 1985;312:674
Reznik J, IJROBP 2005;61:163
Fisher B, JCO 1996;14:1982
Fisher B, JNCI 1996;88:1529

40. TRIAL OPTIONS ALLIANCE - cT1-3 N1 - NACT then +SLN
- ALND + Nodal irradiation vs. Nodal Irradiation
- Z11 after NACT
NSABP B-51
- NACT then – axillary nodes (SLN or ALND)
- No nodal Irradiation vs. Nodal Irradiation
- Omit nodal radiation in pCR patients
Our deliberation is the role and impact of RDT use or nonuse in the residual undissected axilla in patients were only the SLN is performed. These two trials are designed to investigate the role of RDT and surgery among patients with initial biopsy proven disease and residual or non residual disease after NACT.

41. AUTHOR Thompson, 2007 Nos, 2007 Boneti,2008 Ponzone, 2009 Boneti,2009
No. Patients
Blue Node Identification %
%Crossover
No. Patients Neoadjuvant Tx
%Blue node positivity
Thompson, 2007 40 61
Nos, 2007 21 71 - 7
Boneti,2008
131
3.9
Ponzone, 2009 49 55 11
Boneti,2009
220
2.8
Casabona, 2009 72 45
Bedrosian, 2010 30 50 22 13
Noguchi, 2010 20 88 14 43
Rubio, 2011 36 83 29

42. personalizedcancertherapy..org

44. Local Regional Recurrence Among Patients with pCR
Breast conserving therapy, n = 751
, with trastuzumab
Five-year local-regional recurrence
HER2+ pCR vs not
2.6% vs 13.3%
TN pCR vs not P =0.007
1.4% vs 10.1%
LRR rates among pts w pCR are extremely low. On multivariate analysis, the HR-/HER2- subtype, clinical stage III disease, and failure to experience a pCR were associated with LRR.
Swisher et al, Ann Surg Onc 2015

45. 2016 Forward
How will we safely select patients for avoidance of breast surgery after neoadjuvant therapy?
While trying to increase BCS rates in some subgroups, historically driven to mastectomy, on the other hand we are moving forward to avoid surgery in other subgroups

46. Eliminating Breast Cancer Surgery in Exceptional Responders with Neoadjuvant Therapy
Eligibility
Desires BCT
T1/T2 unicentric TN and HER2+
Clinical (ultrasound) N0 at presentation
Neoadjuvant chemotherapy w anti-HER2
Imaging complete or near complete
Question re size remaining calcs absolute or plan to sample 90% (THEREFORE without extensive microcalcifications)

48. 2018

49. 2018- THE END OF AN ERA FOR ALND?
Inflammatory and extensive LABC w/o major response
Axillary Recurrence
Clinically node negative axilla with positive SLN:
in mastectomy patients w/o PMRT- not all!!!
In BCT patients not meeting Z11 criteria
Does ALND for SLN + patients change systemic treatment, reduce local recurrence or improve survival?
It is clear that ALND plays a role in breast cancer for prognosis, for adiding or not RDT and for local control although there no therapeutic role for ALND in many situations where it was useful a decade ago. So the question remains….