The document provides an outline for a presentation on the current operative management of early breast cancer. It discusses the historical perspectives on breast cancer treatment, definitions of early breast cancer, considerations for surgical options, and landmark trials that have influenced current guidelines. It also covers topics like diagnosis and staging, neoadjuvant treatment, management of stage 0 disease, operative techniques for breast conservation and mastectomy, reconstruction options, adjuvant therapy, and follow-up. The aim is to achieve a cure while preserving aesthetics and quality of life according to evolving clinical guidelines.

1. Current Operative
Management of
Early Breast cancer
Dr. Oladele Situ MBBS, MWACS, MRCS
(Snr. Registrar in General Surgery, National Hospital Abuja)
Dr. Oluwole Olaomi FWACS, FICS, FACS, FMCS (supervisor)
Date: May 2020

2. Outline
1. Introduction
2. Brief historical perspective
3. What is early breast cancer?
4. Considerations in operations of early
breast cancer and aim on therapy
5. Landmark trials influencing current
operative management of EBC
6. Diagnosis(presentation, History,
Exam) and staging
7. Neoadjuvant treatment
9. Management of Stage 0 disease &
axillary management Guideline
10. Operative options in EBC management
(OPBS and reconstructive BCS)
11. Adjuvant therapy
12. EBC in the elderly
13. prognosis
14. follow-up
15. Summary
16. References

3. Introduction
• Most common cancer in women, average age 44 in Nigeria (Enugu),
with majority presenting with stage III/IV in Nigeria (61% A.R.K
Adesunkanmi et al, 64% S.N.C Anyanwu)
• Guidelines in the management of EBC is rapidly evolving and changing
due to intense clinical research over the last 40yrs
• Current changes in the Management of Early breast cancer (EBC)
involves changes in tumor diagnosis, localization, OPBS indications
and management of the axilla
• Aim of treatment is to achieve cure while preserving aesthetics

4. Brief historical perspective
• Celsus and Galen:
• “…We attempt to excise the tumor in
a circle where it borders on the
healthy tissue.”
• Moore and Banks (1877):
• Advocated for routine ALND
• Halstead and Meyer (1894):
• Radical Mastectomy
• Czerny(1895):
• true breast reconstruction by using
lipoma
• Haagensen and Stout (1940s):
• “grave signs”
• Harold Gillies (1942): started
pedicled flap for reconstruction
• Patey and Dyson, 1948 (Middlesex
Hospital, London)
• advanced operable breast cancer

5. What is early
breast cancer
(EBC)?
• Stage 0 disease: LIN, DIN, Paget
• Stage 1: T1 N0 M0
• stage 2: T1-2 N0-1 M0
• Small (≤5cm) free tumor with or without free ipsilateral
level I/II node

6. Considerations in Operative options for early
breast cancer
• Diagnostic/therapeutic; Palpable/non-palpable
• Breast size/ Breast Morphology/ location of tumor/ tumor biology/
axillary lymph node status
• Multidisciplinary and patient must be carried along
• Systemic therapy concerns (neoadjvant and adjuvant)
• Aesthetic concerns
• Age, activity level, gender, co-morbidities
OVERVIEW: screen/diagnose, stage, neoadjuvant Chemo, surgery + Axillary
management, reconstruct, adjuvant therapy, follow-up!

7. Aim of early breast cancer management
• Achieve a cure:
• Tumour excision with good
oncologic margin
• Identification and treatment of
metastatic axillary nodes if present
• Prevent recurrence:
• Neoadjuvant Chemotherapy
• Adjuvant radiotherapy
• Adjuvant chemotherapy
• Adjuvant hormonal treatment
• Preserve body image
• Oncoplastic options
• Prevention
• Screening
• Genetic counselling

8. Landmark Trials Shaping the
Current Operative management
of Early Breast cancer

9. MAINLY COMPARES RADICAL MASTECTOMY TO TOTAL MASTECTOMY ALONE
• Primary outcomes: Local Recurrent Rate (LRR), Disease free survival (DFS), Distant Disease-Free Survival (DDFS)
and overall survival (OS)
• Less aggressive mastectomies had similar outcomes with Halsted radical mastectomy
• Routine ALND for patients with a clinically node negative axilla is unnecessary
The National Surgical Adjuvant Breast and Bowel Project (NSABP) Trials
NSABP B-04 Trial

10. • MAINLY COMPARES TOTAL MASTECTOMY WITH BREAST CONSERVING SURGERY (BCS)
a randomized prospective trial comparing lumpectomy and ALND with or without breast irradiation (50Gy without a
boost) with total mastectomy and ALND (modified radical mastectomy) in patients with tumors 4 cm or less
• Total mastectomy was not better than BCS
• Inclusion of radiotherapy was associated with fewer late disease recurrence
• No consensus on the optimal margin width. “No ink on tumor” was the gold standard
The National Surgical Adjuvant Breast and Bowel Project (NSABP) Trials
Later trials in Milan show similar results & recent studies in Texas show even fewer local chest wall recurrences in BCS group
NSABP B-06 Trial

11. COMPARES (BCS + TAMOXIFEN) WITH (BCS + RADIOTHERAPY) IN PATIENTS WITH EBC ≤1CM
• CONCLUSION:
• EBC patients with ≤1cm tumor (ER+) undergoing BCS + Tamoxifen had Higher
Ipsilateral Breast tumor recurrent rate that those having BCS + adjuvant
radiotherapy
The National Surgical Adjuvant Breast and Bowel Project (NSABP) Trials
NSABP B-21 Trial

12. NSABP B-32 trial: role of SLN in EBC
• Histopathologic LN exam remains gold
standard
• SLNB encouraged at least for staging
(about 75% of routine ALND was
unnecessary)
• ALND has comparable therapeutic
value to Axillary radiation
NSABP B-17: BCS in localized DCIS
• Radiotherapy still significantly
decreases the rate of invasive and
non-invasive IBTR in patient with In-
situ Carcinoma
The National Surgical Adjuvant Breast and Bowel Project (NSABP) Trials

13. WBI or PBI?-NSABP and RTOG (NSABP B-39/RTOG
0413) on-going trials
• WBI was not better than PBI in women with EBC
• Though small, radiotherapy side effects were more common for PBI than WBI

14. Diagnosis: presentation, history, exam.
• History & presentation:
• Screen or SBE?
• Unilateral or bilateral?
• Axillary swellings?
• Family history/genetic history?
• Previous breast biopsies/surgery?
• Smoking, comorbidities?
• Age, marital status
• Occupation (model?, athlete?)
• Patient expectations
• Physical exam:
• Palpable or non-palpable
• Location of palpable tumor
• Features of pagets
• Number and location of prior
biopsy scar
• Axillary node status
• Rule out metastasis and co-
morbidities
• Overall breast morphology

15. Breast morphology & The Wise markings

16. Diagnosis, Staging & co-morbidities
Diagnosis
• Digital Mammography
• USS
• Biopsy + IHC
• MRI/CT/PET (in palpable ALN)
• Genetic Screening
Staging
• FBC
• EUCr
• CXR
• LFT + ALP + Ca2+
• Abdominal USS
Other Issues and comorbidities
Pregnancy
DM, HTN, SLE, allergies to dyes and silicon
Risk of other malignancies
Recurrence?

17. Diagnostic Surgical techniques for non-palpable
breast cancer: tumour localisation
Needle/wire localization
Bracket localization
Radio-active seed localization I125

18. Diagnostic Surgical techniques:Tumour biopsy
• Stereotactic
• Core-needle biopsy
• Vacuum aspiration biopsy
• Marker deposition e.g I125 Seeds

19. Axillary staging: SLNB (NSABP B-32)
In active clinical use
• Methylene blue
• Radio-isotopes
• Sulphur colloids
• Combination
Emerging techniques
• Dye localization: ICG
• Contrast enhanced USS with
Microbubbles
• Supramagnetic Iron Oxide
Particles

20. Neoadjuvant Treatment
Allows for better BCS
B-18: AC (doxorubicin + Cyclophosphamide)
B-27: T(docetaxel) + AC

21. Management of Stage 0 disease
DIN
1. Small, unifocal with ↓grade
Needle localization + WLE (1cm) +
Radiotherapy ± Hormone
2. Extensive, unifocal with ↓grade
Bracket localization + QUART +
SLNB ± adjuvant tamoxifen/AI
3. Extensive, multicentric/↑grade
Simple mastectomy + SLNB ±
immediate reconstruction
LIN
• Lifelong surveillance
• Chemoprevention with tamoxifen
or raloxifene or AI
• Prophylactic mastectomy

22. Stage 0 breast neoplasia:
BCS vs OPBS vs
mastectomy?
• Extensive DCIS (>4cm) with
microcalcifications
• Multicentricity
• Inability to achieve negative
margin
• Contraindication to breast
conservation

23. ACOSOG Z0011 Trial (1999-2004):
to determine whether all patients with a positive SLN need an ALND
• RESULTS:
• “…no trend toward clinical benefit of ALND for patients with limited nodal disease”

24. METHODS: In this multicentre, randomised, non-inferiority, phase 3 trial, in patients who had clinically
non-palpable axillary lymph node(s) and a primary tumour of ≤5 cm and who, after SLNB, had one or
more micrometastatic (≤2 mm) SLNs with no extracapsular extension.
CONCLUSION: Axillary dissection could be avoided in patients with early breast
cancer and limited sentinel-node involvement, thus eliminating complications
of axillary surgery with no adverse effect on survival.

25. Following ACOSOG Z0011 and International Breast
Cancer Study Group (IBCSG) 23-01 Trial
CURRENT TREATMENT DICISION MAKING AFTER AXILLARY SLNB (adopted by NCCN/ESMO/ASCO/ASBS)
A. Negative SLNB No further Treatment
B. Positive SLNB (≤2 nodes)
< 5cm tumour
BCS planned
To do Whole Breast radiotherapy
No prior systemic therapy
MEETS ALL CRITERIA No further treatment
AFTER REMOVAL of SLN
C. Positive SLNB (>2 nodes)
> 5cm tumour
For Mastectomy
Prior systemic therapy
No radiotherapy planned
Clinically palpable nodes
MEETS ANY CRITERIA ALND level 1 & 2
D. SLN cannot be Identified ALND level 1 & 2

26. • RESULT AND CONCLUSION:
Occult micro-metastases detected by IHC in SLNs that are negative on
H&E staining has no clinical benefit.
Bone marrow metastases were not associated with increased recurrence

27. “Sentinel lymph nodes should be sectioned as close to 2 mm as
possible and entirely submitted for histologic examination (regardless
of node size)”
By the time a tumor is 0.6-1cm, 10-20% would have an axillary metastasis
“Although there is no minimum number of nodes that should be recovered in
an ALND specimen, 16 nodes should be regarded as a target to ensure a
high level of confidence that the nodes are negative.” Somner et al.
Edinburgh Breast Unit
Somner et al. J Clin Pathol 2004;57:845–848.
doi: 10.1136/jcp.2003.015560

28. Operative options in early breast cancer
Cancer removing Surgeries
1. partial mastectomy/BCS
2. Total Mastectomy
1. Simple
2. Skin paring
3. Nipple-areolar sparing
Reconstructive/oncoplastic surgeries
A. Volume displacement (“breast
rearrangement”/mastopexy)
B. Volume replacement
i. Immediate, delayed immediate
or delayed
ii. Autologus tissue (free or
pedicled) or implants
iii. Fat grafting
iv. Combination
v. Nipple-areolar interventions

29. Sorting out technical meanings/definition in
operative options of early breast Ca
BCS
Oncoplastic
Surgery
“3rd arm”
Total
mastectomy
Partial breast reconstruction
With volume displacement or
Volume replacement oncoplastic
Surgery technique
Total breast reconstruction
With a volume replacement
Oncoplastic Surgery technique
up to 50% of breast
volume can be resected
without loss of oncological
safety
About 30% of patients
undergoing BCS would
require some form of
reconstruction

30. BCS ≠ Oncoplastic surgery
BCS
Oncoplastic
Surgery

31. Definition and Indications for Oncoplastic
Breast surgery (OPBS)
• Significant skin loss
• ≥ 10% (20-30%) breast volume loss
• Locations with unfavorable cosmetic
outcome e.g Infra-nipple line,
medial, central
• stage I and II breast cancer
• unifocal disease
• Not known BRCA mutation carriers
• Radiotherapy available
• Lump ≤ 4-5cm
• Follow-up possible
• OPBS may be defined as breast
surgery focusing on optimizing
both oncologic and aesthetic
outcomes, irrespective of the
type(s) of surgery performed
OPBS: Current Gold standard if
negative tumor margin is achievable
+ radiotherapy
Are these still contraindications?

32. Results of voting at the 2013 St. Gallen International Breast Consensus
meeting regarding whether a range of controversial clinical scenarios
would be viewed as a contraindication to breast conservation surgery
-Goldhirsch et alAnn Oncol. 2013;24(9):2206–23.
Yes(%) No(%) ? (%)
Extensive microcalcification 20 74 6
Multifocality 7 89 4
Multicentricity 30 65 5
Close to nipple-areolar complex 0 96 4

33. A. Cancer removing surgeries:
MASTECTOMIES: series 1
a) NSM inframammary,
b) SSM circumareolar,
c) SSM circumareolar with lateral
extension,
d) SSM elliptical
(a) (b)
(d) (c)

34. A. Cancer removing surgeries:
MASTECTOMIES: series 2
a) NSM lateral crease,
b) NSM periareolar with lateral
extension,
c) skin reducing +/− dermal sling,
d) SSM trans-vertical
(a) (b)
(d) (c)

35. Decision making tree in type of mastectomy
based on the breast volume and ptosis

36. B. Oncoplastic options: Volume displacement
(therapeutic mammoplasty/ Mastopexy/ breast rearrangement)
Level 1:
Dual plane undermining usually without skin loss
Direc skin closure after moderate (<20%) volume loss
Usually no special training required. Good for dense
breast
• Doughnut mastopexy
• Round block mastopexy
• Batwing mastopexy
• Vertical scar (Lejour) mastopexy
• Inverted T mastopexy
• Goldilock’s mastopexy
Level 2:
Usually posterior plane undermining
Extensive skin and volume (20-50%) loss resulting in
smaller rounder breast (mammoplasty)
Special OPBS training required. Dense & Fatty breasts
• Hall Findley mastopexy
• Grisotti mastopexy
• Inferior pedicled breast flap
• J-mammoplasty
• V-mammoplasty

37. B. Oncoplastic options based on tumor location

38. Batwing Mastopexy (Upper pole disease)

39. Inverted T-Mastopexy (for lower pole disease,
now being considered for all quadrants)

40. Doughnut & round block mastopexy procedure
(any quadrant disease)

41. Vertical Scar Mammoplasty (Lejour) for
Central Breast cancer
After NAC
Tatoo

42. Goldilock’s Mastectomy The vertical Hall Findlay
Nipple is sacrificed

43. Grisotti mastopexy (Central breast cancer)

44. V-Mammoplasty for inferomedial Dx (LIQ)

45. Racquet Mammoplasty (OUQ)

46. What margin width is enough?
• For Invasive Cancer = Consensus
guidelines support “no ink on
tumor”
• For DCIS = a margin of 2mm
provided adjuvant radiation therapy
is considered
-(SSO-ASTRO-ASCO DCIS margins consensus panel)
• “Wider margins has not been proven to
provide added benefit”
• Melisa et al. Cancer. 2018 April 01; 124(7):
1335–1341. doi:10.1002/cncr.31221.
Memorial Sloan K Cancer Center.

47. Advantage of OPBS
• Tumor negative margins
• Lesser re-excision rates
• Lesser mastectomies
• Better self image confidence
In Oncoplastic BCS, an average of 200 g up to 1000 g or more
can be removed from a medium to large sized breast during
BCS with no cosmetic compromise

48. OPBS outcomes- How safe?
prospective analysis of a series of 100 patients undergoing level II OPS
demonstrated 5-year overall and disease-free survival rates of 95.7% and 82.8%
respectively
-Clough KB, Lewis J, Couturaud B, et al. Oncoplastic Techniques allow extensive resections for
breast-conserving therapy of breast carcinomas. Ann Surg. 2003;237(1):26–34
The pT2 and pT3 combined group had a 5-year local recurrence rate of 8% and a
mortality rate of 15%. The overall local recurrence rate was determined to be 3%
-Rietjens M, Urban CA, Petit JY, et al. Long-term oncologic results of breast conservation
treatment with oncoplastic surgery. Breast. 2007;16(4):387–95.

49. Reconstructive breast surgery: Timing
• Immediate
• Delayed
• Immediate delayed
Immediate reconstruction followed by radiation has complication rates of 87% versus 8.6% in
those that have delayed reconstruction after radiation therapy

50. Alloderm Sling:
Porcine dermal allograft
Human dermal allograft
Bovine dermal allograft

51. Considerations in implant-based surgery
Indication for Implant based surgery
• Bilateral
• augmentation
• Short surgery
• Deficient donor site
• scars
• Small breast mound
Relative contraindication for implants
• Young age (may need an implant
replaced multiple times)
• Patient unwilling to adhere to follow-
up
• Very large or ptotic breast
• Silicon allergy
• Implant fear
• Previous failed implants
• Need for adjuvant radiation therapy

52. Autologous flaps: Types
Abdominal Based Flaps
1. Free flap or Pedicled (Single
pedicle/Double pedicle)
2. Vertical or TRAM
3. Deep inferior epigastric
perforator flap (DIEP)
4. Upper abdominal horizontal flap
5. Tubed abdominal flap
6. Latissimus dorsi
musculocutaneous
Gluteal flaps
• Gluteal artery perforator flaps
(IGAP/ SGAP)

53. Autologous Flaps: TRAM and its modifications
Vascular territories of the abdominal
wall
Robbins 1979 (vertical); Hartrampf 1982 (Transverse)
Gold standard. Feels like breast tissue
Indicated in breast of all sizes and ptosis

54. Autologous Flaps: LDF
Indications
• Abdominal donor site
unavailable, Small breast with
minor breast ptosis
• Salvage of previous breast
reconstruction
Contraindications
• Previous lateral thoracotomy,
• Bilateral reconstruction
• Significant breast ptosis

55. Autologous Flaps: Gluteal artery Perforator
(GAP) flaps
• Originally a myocutaneous flap
• Inferior GAP flap
• Superior GAP flap
• Patients with ‘thin’ abdominal wall
• Difficult dissection with short
small caliber vessels

56. Transverse Upper Gracilis (TUG) flap
• based on the ascending branch of
the medial circumflex femoral
artery
• For immediate reconstruction of
small-moderate sized breast
• Easier than GAPF and TRAM
• Relatively smaller tissue with short
vascular pedicle

57. Nipple areolar Options: reconstruction, graft
prothesis and tattoos
• Setbacks:
• Poor cosmetic outcome
• Necrosis
• Can harbor cancer cells
• Insensate

58. Indications for fat grafting (usually done after
4-6months of initial surgery)
• Correction of contour or volume
defects after mastopexy,
stimulates neovascularization in
irradiated breast and pliability of
scar tissue. Cover, disguise
capsular contracture
• Injected volume ↓by 30% (up to
50%)
• Transferred fat retains ‘memory’
of donor site

59. 6-month Lipo-remodeling result after left LD
reconstruction (300cc on left and 150cc on right)

60. Adjuvant therapy
• Radiotherapy
• Conformal and field coverage < 8weeks post-Op
• WBI or PBI (brachytherapy), role of hyperthermia
• Boost (10-16Gy)
• Systemic therapy
• Chemotherapy
• Hormonal
• Targeted

61. What about women ≥70yrs with EBC?-
The Cancer and Leukaemia Group Trial
Conclusion: “Tamoxifen remains a reasonable option for
women age ≥ 70 years with ER-positive early-stage breast
cancer.” thus radiotherapy (QUART) can be avoided

62. Recent operative advances in Axillary
Management of EBC
• There was ↓incidence of:
• Lymphedema, Nerve damage, drain usage, length of hospital stay, time to resumption
of normal day-today activities

63. Aim: to determine whether all patients with a positive SLN need an ALND
• Methodology:
• ASCOG Z0011 trial (1999 – 2004), 891 patients randomized (446 to SLNB alone; 445 to SLNB +
ALND). The patients were randomized to ALND or no further surgery
• Enrolled patients with clinical T1 or T2, N0, M0 breast cancer who underwent BCT and were
found to have one or two positive SLNs by H&E evaluation
• All patients received WBI (third-field axillary irradiation was not done)
• The primary endpoint was OS and secondary endpoint was DFS
• RESULTS:
• “…no trend toward clinical benefit of ALND for patients with limited nodal
disease”

64. Prognosis and Follow-up
• Axillary status
• Surgical margin status
• Age
• Tumor biology
• Tumor size
• Genetic risk factor
• Adjuvant treatment option
• Follow up
Carter CL, Allen C, Henson DE. Relation of tumour size, lymph node
status, and survival in 24,740 breast cancer cases. Cancer 1989;63:181–7

65. Will anything change in the future?
• Awaiting the Full Result report of ASOCOG Z0011 trial
• Can selected patients undergoing total mastectomy avoid routine ALND?
• Early result of AMROS (After Mapping of the Axilla: Radiotherapy or
Surgery?) trial
• Can we offer radiotherapy in place of routine ALND in EBC patients with
tumor ≤3cm with limited positive SLNB result?

66. Summary
• Do Neoadjuvant chemo + BCS + adjuvant radio + systemic therapy
• BCS and Breast reconstruction are major part of management of early
breast cancer
• Landmark Trials have largely re-shaped the current trends in the
management of EBC
• Newer advances in tumor localization
• Contraindications for BCS/OPBS has changed due to newer techniques
• Axillary management in diagnosis and treatment has changed
• Neoadjuvant chemo has no significant effect on the reconstruction
outcome.

67. Key References
 Wyld L, Markopoulos C, Leidenius M, Senkus-Konefka E, editors. Breast
Cancer Management for Surgeons: A European Multidisciplinary
Textbook [Internet]. Cham: Springer International Publishing; 2018
[cited 2020 May 2]. Available from:
http://link.springer.com/10.1007/978-3-319-56673-3
 Clough KB, Kaufman GJ, Nos C, Buccimazza I, Sarfati IM. Improving
Breast Cancer Surgery: A Classification and Quadrant per Quadrant
Atlas for Oncoplastic Surgery. Ann Surg Oncol. 2010 May;17(5):1375–
91.
 Black DM, Mittendorf EA. Landmark Trials Affecting the Surgical
Management of Invasive Breast Cancer. Surg Clin North Am. 2013
Apr;93(2):501–18.
 Mamounas EP. NSABP Breast Cancer Clinical Trials: Recent Results and
Future Directions. Clin Med Res. 2003 Oct 1;1(4):309–26.
 Galimberti V, Cole BF, Zurrida S, Viale G, Luini A, Veronesi P, et al.
Axillary dissection versus no axillary dissection in patients with
sentinel-node micrometastases (IBCSG 23–01): a phase 3 randomised
controlled trial. Lancet Oncol. 2013 Apr;14(4):297–305.
 Mascaro A, Farina M, Gigli R, Vitelli CE, Fortunato L. Recent advances in
the surgical care of breast cancer patients. World J Surg Oncol.
2010;8(1):5.
 Giuliano AE, McCall L, Beitsch P, Whitworth PW, Blumencranz P, Leitch
AM, et al. Locoregional Recurrence After Sentinel Lymph Node Dissection
With or Without Axillary Dissection in Patients With Sentinel Lymph Node
Metastases: The American College of Surgeons Oncology Group Z0011
Randomized Trial. Trans Meet Am Surg Assoc. 2010;128:12–21.
 Rostas JW, Dyess DL. Current Operative Management of Breast Cancer: An
Age of Smaller Resections and Bigger Cures. Int J Breast Cancer.
2012;2012:1–7.
 Hunt KK, Ballman KV, McCall LM, Boughey JC, Mittendorf EA, Cox CE, et al.
Factors Associated With Local-Regional Recurrence After a Negative
Sentinel Node Dissection: Results of the ACOSOG Z0010 Trial. Ann Surg.
2012 Sep;256(3):428–36.
 Hughes KS, Schnaper LA, Bellon JR, Cirrincione CT, Berry DA, McCormick B,
et al. Lumpectomy Plus Tamoxifen With or Without Irradiation in Women
Age 70 Years or Older With Early Breast Cancer: Long-Term Follow-Up of
CALGB 9343. J Clin Oncol. 2013 Jul 1;31(19):2382–7.
 Fitzgibbons PL, Page DL, Weaver D, Thor AD, Allred DC, Clark GM, et al.
Prognostic Factors in Breast Cancer. Arch Pathol Lab Med. 2000;124:13.
 Mansel RE, Fallowfield L, Kissin M, Goyal A, Newcombe RG, Dixon JM, et
al. Randomized Multicenter Trial of Sentinel Node Biopsy Versus Standard
Axillary Treatment in Operable Breast Cancer: The ALMANAC Trial. JNCI J
Natl Cancer Inst. 2006 May 3;98(9):599–609.

68. THANK YOU