SLN in micro-metastasis & contralateral mastectomy

1. Journal Club

2. Randomised controlled trial comparing
axillary dissection versus no axillary
dissection in patients with sentinel
node micrometastases
Published in final edited form as:
Lancet Oncol . 2013 April ; 14(4): 297–
305

3. Introduction
• For breast cancer patients with a metastatic
sentinel node (SN), axillary dissection (AD) has
been standard treatment.
• However, for patients with minimal SN
involvement, AD may be overtreatment.
• Trial was designed to determine whether no
AD is noninferior to AD in patients with one or
more micrometastatic (≤2 mm) SNs and
tumour ≤5 cm.

4. • The first randomised trial to validate sentinel node
biopsy (SNB) in breast cancer was published in 2003.
• This trial and others confirmed that SNB accurately
stages the axilla, so that if the sentinel node (SN) is
uninvolved the other axillary nodes are disease-free
with high probability and the patient can be spared
axillary dissection (AD).
• If the SN is involved by metastasis, standard practice at
the time was to perform AD (levels I and II in the
United States, and all three Berg levels in many
European countries ).

5. • AD removes any disease within the axilla – after
which disease recurrence in the axilla is almost
unknown – and may also have a favourable effect
on survival, although this has never been proven;
• Its main use was as a disease staging procedure.
• However short and long-term side effects of AD
have always been a concern.
• These include lymphedema, pain, and reduced
arm movement.

6. • SNB very quickly became an integral part of the
conservative treatment of breast cancer because it
permitted avoidance of AD in a large proportion of
patients, with early breast cancer, while still providing
information to guide adjuvant treatment.
• However, with the development of SNB came new and
more exhaustive methods of evaluating the SN in order
to ensure that any disease there was not missed.
Whereas around three sections per axillary lymph node
were typically examined in the pre-SNB era, the entire
SN was serial sectioned and all sections examined.

7. • This evaluation resulted in the frequent
identification of micrometastatic foci (≤2 mm
in diameter) and isolated tumour cells (ITCs),
whose prognostic significance was uncertain.
• We hypothesised that in patients with
micrometastases only in the SN, AD might be
overtreatment; we designed the multi-centre
randomised controlled trial to determine
whether this was the case.

8. • Specifically the trial was designed to compare
outcomes in patients with SN
micrometastases treated with AD, with
outcomes in those receiving no further
treatment to the axilla.
• The primary study endpoint was disease-free
survival (DFS) but we were also interested in
axillary recurrence rates and axillary surgery
complication rates in the two arms.

9. Study design and patients
• A two-arm, multicentre, randomised, non-
inferiority, phase 3 trial comparing no AD with
AD in breast cancer patients with sentinel
node micrometastases.
• Patients were recruited from 27 institutions
between April, 2001, and February, 2010

10. Eligible candidates
• Women eligible for registration could be any age
with clinical, mammographic, ultrasonographic,
or pathological diagnosis of breast cancer,
provided they had no previous or concomitant
malignancy, pure ductal carcinoma in situ,
• previous systemic therapy for breast cancer,
cancer chemoprevention treatment in the
• preceding year, distant metastases, palpable
axillary nodes, or Paget’s disease without nvasive
cancer.

11. • Patients could be scheduled for mastectomy or
conservative breast surgery.
• They were included in the trial and randomised if,
during or following surgical treatment for breast
cancer, they were found to have a tumour ≤5 cm
in maximum diameter by pathological
measurement of the surgical specimen, and one
or more micrometastatic (≤2 mm) foci in the SNs,
but no macrometastatic disease.
• We included ITCs within the definition of
micrometastatic.

12. • Patients were randomly allocated in a 1:1
ratio to AD or no AD using permuted blocks
generated by a congruence algorithm

13. • The SN could be examined in either of three ways:
• (a) Preoperatively under local anaesthesia; if the
patient had a micrometastatic node and was
randomised to AD, she received AD during the
operation to remove the primary.
• (b) Intra-operatively, with intraoperative SN
examination, and AD performed during the operation
to remove the primary.
• (c) Intra-operatively with later histological examination,
and later second surgery under general anaesthesia if
randomised to AD.

14. • All SNs were entirely sectioned at 50–200 μ m
intervals and each section (frozen or
permanent) was examined by haematoxylin
and eosin staining.
• Cytokeratin immunostaining was used only
when the presence of micrometastasis was
suspected but not certain, or not determined,
on haematoxylin and eosin-stained sections.

16. Results
• A total of 6681 patients were registered for the
trial prior to surgery between 4 April 2001 and 1
February 2010.
• Of these, 934 patients (14% of those screened)
from 27 clinical centres were randomised after
informed consent and determination of eligibility,
especially with respect to micrometastatic
involvement of sentinel lymph nodes.
• Of these, 583 (62%) were from the European
Institute of Oncology, Milan.

18. Statistics

24. Comparison of axillary dissection (AD, solid line) to no
axillary dissection (No AD, dashed
line) for disease-free survival

25. Cumulative incidence of breast cancer
events

26. Overall survival

30. Discussion
• At a median follow-up of 5.0 years, we found
no difference between the AD and no AD arms
for the primary endpoint of DFS.
• Most patients in our study had tumours less
than 3 cm (92%), received breast conserving
surgery (91%) and adjuvant systemic therapy
(96%), and thus our results are most directly
applicable to these patient subpopulations.

31. • Furthermore there was a reassuringly low rate of
disease recurrence in the un-dissected axilla
(<1%),
• However non-sentinel axillary nodes were
metastatic in 13% of the AD arm.
• The discrepancy between the low rate of axillary
recurrence in the no AD arm and the high rate of
axillary involvement in the AD arm may be due to
systemic treatment and whole breast irradiation,
both of which can eliminate low volume axillary
metastasis

32. • Furthermore biologic characteristics of the
primary tumour, such as hormone receptor
expression, HER2 status, and tumour
proliferation rate (e.g., Ki67 labelling index),
substitute the prognostic information formerly
provided by axillary status.

33. Conclusion
• AD in patients with early breast cancer
represented in this study (most had tumours <
3 cm (92%; 856/931), received breast
conserving surgery (91%; 845/931) and
adjuvant systemic therapy (96%; 892/931))
should be avoided when the SN is minimally
involved, thus eliminating complications of
axillary surgery with no adverse effect on
survival.

34. References
• 1. Veronesi U, Paganelli G, Viale G, et al. A randomized comparison of sentinel-node biopsy with
• routine axillary dissection in breast cancer. N Engl J Med. 2003; 349:546–53. [PubMed: 12904519]
• 2. Krag D, Weaver D, Ashikaga T, et al. The sentinel node in breast cancer–a multicentre validation
• study. N Engl J Med. 1998; 339:941–6. [PubMed: 9753708]
• 3. Straver ME, Meijnen P, van Tienhoven G, et al. Sentinel node identification rate and nodal
• involvement in the EORTC 10981-22023 AMAROS trial. Ann Surg Oncol. 2010; 17:1854–61.
• [PubMed: 20300966]
• 4. Veronesi U, Viale G, Paganelli G, et al. Sentinel lymph node biopsy in breast cancer: tenyear
results
• of a randomized controlled study. Ann Surg. 2010; 17:1854–61.
• 5. Lyman GH, Giuliano AE, Somerfield MR, et al. American Society of Clinical Oncology. American
• Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in
earlystage
• breast cancer. J Clin Oncol. 2005; 23:7703–20. [PubMed: 16157938]
• 6. Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no axillary dissection in women
• with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA. 2011;
• 305:569–75. [PubMed: 21304082]

35. Predictors of Contralateral Breast Cancer in
Patients With Unilateral Breast Cancer
Undergoing Contralateral Prophylactic
Mastectomy
Published in Cancer Volume 115, Issue
5, pages 962–971, 1 March 2009

36. Introduction
• Although contralateral prophylactic mastectomy
(CPM) reduced the risk of contralateral breast
cancer in unilateral breast cancer patients, it was
difficult to predict which patients were most
likely to benefit from the procedure.
• The objective of this study was to identify the
clinicopathologic factors that predict contralateral
breast cancer and thereby inform decisions
regarding performing CPM in unilateral breast
cancer patients

37. Introduction
• Women who carry a germline mutation in either the BRCA1 or
BRCA2 gene have a lifetime risk of breast cancer of 60-70%,1
and once diagnosed as having breast cancer, have a high risk
of a second primary breast cancer.
• The principal goal of treating hereditary breast cancer is to
minimise the likelihood of patients dying from a first breast
cancer, but it is also important to minimise the incidence of,
and mortality from, a second primary cancer.

38. • Traditionally, breast cancer trialists and clinical
epidemiologists focus their attention on the 10 year
period after diagnosis, because this is when the
majority of cancer related deaths occur.
• However, a mortality benefit from preventing a second
primary breast cancer is unlikely to be apparent within
this narrow interval, given that second primary cancers
accumulate slowly and for an extended period.
• Little information is available on the long term survival
experience of women with a BRCA1 or BRCA2 mutation
who are treated for breast cancer.

39. • Most previous studies involve a small number of
participants or follow them for a short period,
and no previous study has looked at mortality in
association with mastectomy of the contralateral
breast.
• In North America, approximately half of women
with a BRCA mutation will undergo mastectomy
of the contralateral breast to prevent a second
breast cancer, but it has not yet been shown that
contralateral mastectomy reduces breast cancer
related mortality.

41. Materials & Methods
• We used the Surgical Oncology Breast Cancer
Database to retrospectively evaluate unilateral
breast cancer patients who underwent CPM at
The University of Texas M. D. Anderson Cancer
Center from January 2000 to April 2007. The
M. D. Anderson Institutional Review Board
approved this study.

42. • Patients were included if they had unilateral
primary breast cancer and had no clinical or
radiographic evidence of a contralateral breast
malignancy.
• Patients known to have had bilateral breast
cancer before CPM were excluded
• A total of 542 CPM patients were included in
the study. Some of these patients were
included in a previous report from our
institution.9

43. • Clinical factors examined included patient age,
race, age at menarche, age at first live birth,
number and findings of previous breast
biopsies, family history of breast cancer,
ipsilateral clinical tumor stage, reasons for
CPM, histologic findings for both breasts, and
follow-up status

44. • We classified atypical ductal hyperplasia (ADH),
atypical lobular hyperplasia (ALH), and lobular
carcinoma in situ (LCIS) as moderate-risk to high-
risk histologic findings.
• The presence of ipsilateral proliferative disease
with atypia (either ductal or lobular) or LCIS in
association with the diagnosed cancer also was
evaluated.
• Additional ipsilateral moderate- to high-risk
lesions were defined as concurrent high-risk
proliferative lesions including ADH, ALH, or LCIS
within the surgical specimen in the ipsilateral
breast.

45. • Mastectomies were performed on the
ipsilateral side with or without lymph node
staging as considered appropriate based on
diagnostic biopsy findings.
• Synchronous or delayed CPM was usually
performed with or without sentinel lymph
node biopsy at the discretion of the operating
surgeon.
• After surgery, the oncologist recommended
adjuvant systemic therapy based on the final
pathology information

46. • Some patients received chemotherapy before
surgery.
• Routine follow-up consisted of patient history
and physical examination of the breast, chest
wall, and regional lymph node basins at 3-
month and 6-month intervals for 5 years
followed by annual examinations for lifetime.
• Imaging studies were performed as needed
based on symptoms and/or physical findings.
Reconstructed breasts were not routinely
imaged.

47. Gail risk
• The Breast Cancer Risk Assessment Tool (the Gail
model) is often used by health care providers to
estimate risk.
• Although the tool can estimate risk, it cannot tell
whether or not patient will get breast cancer.
• The tool calculates a woman's risk of developing
breast cancer within the next five years and
within her lifetime (up to age 90).
• It takes into account seven key risk factors for
breast cancer

48. • Age
• Age at first period
• Age at the time of the birth of her first child (or
has not given birth)
• Family history of breast cancer (mother, sister or
daughter)
• Number of past breast biopsies
• Number of breast biopsies showing atypical
hyperplasia
• Race/ethnicity

49. • Women with a five-year risk of 1.67 percent or higher
are classified as "high-risk." This score (a five-year risk
of 1.67 percent or higher) is the cut-off for the FDA
guidelines for taking a risk-lowering drug (tamoxifen or
raloxifene) to reduce breast cancer risk.
• The Breast Cancer Risk Assessment Tool (the “Gail
model” available at http://www.cancer.gov/bcrisktool/
accessed April 2008, or 800-4-CANCER) was used to
calculate the 5-year Gail risk for each patient in our
study.

50. Case matched control group
• We identified 1574 patients with unilateral
primary breast cancer who did not undergo
CPM and included them as a case-matched
control group.

51. Statistical analysis
• For statistical analysis, patients who underwent
CPM were separated into 3 groups: contralateral
findings of none to low-risk pathology,
contralateral findings of moderate-risk to high-
risk pathology, and contralateral findings of
malignancy on final pathology.
• Data were subjected to univariate analysis and
then multivariate analysis.

52. • Stepwise multiple logistic regression analysis
was used to identify variables that predicted
malignant findings in the contralateral breast.

53. Results

58. Reasons patients underwent
contralateral mastectomy
• The majority of patients (72%) chose to undergo
CPM for 1 or 2 of the following reasons:
• a family history of breast cancer,
• difficulty in surveillance for contralateral breast
cancer because of clinically and
mammographically dense breast tissue or diffuse
indeterminate microcalcifications in the
contralateral breast, and
• psychologic fear of developing another breast
cancer.

60. • Univariate analysis revealed that patient age
and a 5-year Gail risk >1.67%, an ipsilateral
invasive lobular histology an additional
ipsilateral moderate-risk to high-risk pathology
and an ipsilateral multicentric tumor were
shown to be significant predictors of breast
cancer in the contralateral breast

61. • However, patient race, estrogen receptor (ER)
status, progesterone receptor (PR) status,
previous hormone replacement therapy, and
first-degree family history of breast cancer
were not associated with increased
contralateral breast cancer risk.

62. Multivariate Analyses for Contralateral Breast Cancer Between Patients Treated With
or Without Neoadjuvant Chemotherapy
• In patients who did not receive neoadjuvant
chemotherapy, an ipsilateral multicentric tumor
(OR of 3.7; P = .03), and a 5-year Gail risk ≥1.67%
(OR of 4.6; P < .0001) were associated with
contralateral breast cancer.
• In patients who received neoadjuvant
chemotherapy, only an ipsilateral invasive lobular
histology (OR of 21.3; P = .0009) was found to be
associated with contralateral breast cancer.

63. Discussion
• We found that CPM was associated with a low
risk of occult contralateral breast cancer
(4.6%). Based on our analysis, CPM may be a
rational choice for breast cancer patients who
have a 5-year Gail risk >1.67%, an additional
ipsilateral moderate-risk to high-risk
pathology, an ipsilateral multicentric tumor, or
an ipsilateral invasive lobular histology.

64. • Occult contralateral breast cancer ranges from 4.6% to
68% depending on the method of diagnosis.
• Nielsen et al reported that 68% of unilateral breast
cancer patients had evidence of contralateral breast
cancer in 84 consecutive autopsies, whereas
• Wanebo et al, using randomly selected contralateral
breast biopsies, found a rate of 18%.
• Other studies found that 5% of unilateral breast cancer
patients had evidence of contralateral breast cancer.

65. • Our findings are consistent with the lower rate
of contralateral breast cancer findings and to
the best of our knowledge, is 1 of the largest
recent cohorts of CPM patients evaluated for
occult contralateral breast cancer.

66. • In the current study, the rate of contralateral
cancer among women without CPM was 2.4%,
which is close to the 2.7% incidence reported in a
nationwide study of 50,000 women diagnosed
between 1979 and 1999.2 Peralta et al reported a
higher rate of 19.8%.
• We noted 25 incidental contralateral cancers at
the time of CPM compared with an expected 8 to
16 new contralateral cancers based on the known
per-year incidence rates.

67. • This finding suggests that, in our cohort, CPM
led to early detection and resection of already
existing contralateral breast cancers more
than prevention of expected contralateral
cancers.

68. • The risk of developing contralateral cancer is
not the same for all breast cancer patients, so
it is unnecessary to routinely perform CPM in
all patients.
• A recent study showed the rate of CPM for
patients with stages I through III unilateral
breast cancer increased by 150% from 1998 to
2003 in the US.21

69. • The results of the current study provide
additional evidence supporting that patients with
invasive lobular carcinoma are at an increased
risk of developing contralateral breast cancer.
• Our findings are consistent with previous studies
demonstrating that patients aged >50 years of
age at the time of initial breast cancer diagnosis
or with at least 1 affected first-degree relative
have an increased risk of contralateral breast
cancer.

70. • However, the Gail model takes into
consideration other factors in addition to
patient age and family history, and thus may
be a better predictor of increased
contralateral breast cancer risk.

71. • Increased age was also associated with an
increased risk of moderate-risk to high-risk
histologic findings in the contralateral breast on
univariate analysis and multivariate analysis.
• In the current study, a first-degree family history
of breast carcinoma alone was not found to be
associated with an increased incidence of
malignant or moderate-risk to high-risk
contralateral breast findings.

72. • We noted that different factors were observed in
patients receiving neoadjuvant chemotherapy
and those who did not receive neoadjuvant
treatment.
• In patients receiving neoadjuvant chemotherapy,
the association between ILC and contralateral
breast cancer is likely due to the finding that
patients with ILC usually had larger tumors and
were treated with chemotherapy before surgery.

73. • Lehman et al reported that MRI can detect
contralateral cancer that is undetectable by
mammography at the time of the initial breast
cancer diagnosis

74. Contralateral mastectomy and survival after breast
cancer in carriers of BRCA1 and BRCA2 mutations:
retrospective analysis

75. Limitations
• Our study has limitations, including those inherent to
any single-institutional, retrospective study.
• One limitation in this respect is the relatively short
follow-up time.
• Whether the contralateral breast cancer incidence will
remain low in our CPM cohort remains to be
determined.
• Notwithstanding, the results of this study can be
valuable to other institutions with respect to their own
recommendations on the use of CPM in patients with
unilateral breast cancer patients and may be useful in
the design of trials addressing this issue.

76. Conclusion
• In conclusion, we found that unilateral breast
cancer patients who underwent CPM had a low
risk of developing contralateral breast cancer.
• CPM may be a rational choice for breast cancer
patients who have a 5-year Gail risk >1.67%, an
additional ipsilateral moderate-risk to high-risk
pathology, an ipsilateral multicentric tumor, or an
ipsilateral invasive lobular histology

77. • Evaluating 5-year Gail risk and histologic
findings in the ipsilateral breast in unilateral
breast cancer patients may help predict the
likelihood of contralateral breast cancer and
assist in stratifying risk and counseling
patients.

78. References
• 1. Goldflam K, Hunt KK, Gershenwald JE, et al. Contralateral prophylactic mastectomy. Predictors of significant
histologic findings. Cancer. 2004; 101:1977–1986. [PubMed: 15389473]
• 2. Herrinton LJ, Barlow WE, Yu O, et al. Efficacy of prophylactic mastectomy in women with unilateral breast
cancer: a cancer research network project. J Clin Oncol. 2005; 23:4275–4286. [PubMed: 15795415]
• 3. Kollias J, Ellis IO, Elston CW, Blamey RW. Clinical and histological predictors of contralateral breast cancer. Eur J
Surg Oncol. 1999; 25:584–589. [PubMed: 10556004]
• 4. Robbins GF, Berg JW. Bilateral primary breast cancer, a prospective clinicopathological study. Cancer. 1964;
17:1501–1527. [PubMed: 14239677]
• 5. Montgomery LL, Tran KN, Heelan MC, et al. Issues of regret in women with contralateral prophylactic
mastectomies. Ann Surg Oncol. 1999; 6:546–552. [PubMed: 10493622]
• 6. McDonnell SK, Schaid DJ, Myers JL, et al. Efficacy of contralateral prophylactic mastectomy in women with a
personal and family history of breast cancer. J Clin Oncol. 2001; 19:3938–3943. [PubMed: 11579114]
• 7. van Sprundel TC, Schmidt MK, Rookus MA, et al. Risk reduction of contralateral breast cancer and survival after
contralateral prophylactic mastectomy in BRCA1 or BRCA2 mutation carriers. Br J Cancer. 2005; 93:287–292.
[PubMed: 16052221]
• 8. Peralta EA, Ellenhorn JD, Wagman LD, Dagis A, Andersen JS, Chu DZ. Contralateral prophylactic mastectomy
improves the outcome of selected patients undergoing mastectomy for breast cancer. Am J Surg. 2000; 180:439–
445. [PubMed: 11182394]
• 9. Boughey JC, Khakpour N, Meric-Bernstam F, et al. Selective use of sentinel lymph node surgery during
prophylactic mastectomy. Cancer. 2006; 107:1440–1447. [PubMed: 16955504]
• Yi et al. Page 9 Cancer. Author manuscript; available in PMC 2015 March 19. Author Manuscript

79. A Comparison of Clinical Features,
Pathology and Outcomes in Various
Subtypes of Breast Cancer in Indian
Women

84. • In this retrospective study of breast cancer
patients at a tertiary cancer care hospital in India,
according to the IHC subtypes,
• Luminal A had better prognostic features and
survival compared to other subgroups.
• Mainly premenopausal women had Triple
negative breast cancer.
• Patients in the Her 2 enriched subgroup had the
worst prognostic features and the worst survival
amongst all subgroups.

85. • However the survival differences among all
subgroups were not statistically significant.
• A follow-up study after a few years is
warranted to document further differences in
survival, if any.