Recent Updates in Surgical Management of Breast Cancer Asian Patient's Perspective

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1 Recent Updates in Surgical Management of Breast Cancer Asian Patient's Perspective Tokyo-West Tokushukai Hospital Department of Breast Oncology Tokyo-West Tokushukai Hospital, Tokyo, Japan Kaz Sato, MD, PhD

2 Tokyo-West Tokushukai Hospital Extent of Surgery for Cancer

3 Some local treatment comparisons (more surgery vs less surgery) involved little absolute difference in the risk of local recurrence. However, a 20% absolute reduction in 5-year local recurrence leads to a 5% absolute reduction in 15-year mortality (ie, One-in-four rule: one breast cancer death avoided for every four recurrences avoided). Tokyo-West Tokushukai Hospital

4 In trials of systemic therapy, 5 years of tamoxifen reduced the local recurrence rate by about one half in women with ER-positive disease (local recurrence rate ratio 0.47) and polychemotherapy reduced it by about one third (ratios 0.63 and 0.70 for women aged 50 and years, respectively). Tokyo-West Tokushukai Hospital

5 Advances in Systemic Therapies n=3,562 AOR 30 ER+ve ER-ve (%) Tokyo-West Tokushukai Hospital Saphner T, et al. J Clin Oncol 1996

6 Advances in Systemic Therapies ddac P TAC FE100C Doc 14% / 7% 28% / 30% 13% / 23% AC P AC Doc FAC FE100C 17% / 6% 14% / 6% AC CMF 23% / 17% 21% / 23% FE50C No Chemo 28% / 21% ( relative risk: DFS/OS in 5 yrs) Bonadonna G et al. N Engl J Med. 1995;332: ; Citron ML et al. J Clin Oncol. 2003;21: ; Early Breast Cancer Trialists' Collaborative Group. Lancet. 1998;351: ; Early Breast Cancer Trialists' Collaborative Group. Lancet. 1998;352: ; Henderson IC et al. J Clin Oncol. 2003;6: ; Nabholtz JM et al. ASCO 2002; Orlando, Fla.

7 Advances in Systemic Therapies ddac P TAC FE100C Doc 14% / 7% 28% / 30% 13% / 23% AC P AC Doc FAC FE100C 17% / 6% 14% / 6% AC CMF 23% / 17% 21% / 23% FE50C No Chemo 28% / 21% ( relative risk: DFS/OS in 5 yrs) Bonadonna G et al. N Engl J Med. 1995;332: ; Citron ML et al. J Clin Oncol. 2003;21: ; Early Breast Cancer Trialists' Collaborative Group. Lancet. 1998;351: ; Early Breast Cancer Trialists' Collaborative Group. Lancet. 1998;352: ; Henderson IC et al. J Clin Oncol. 2003;6: ; Nabholtz JM et al. ASCO 2002; Orlando, Fla.

8 Breast Surgical Oncology in an Era of Systemic Therapy Systemic tx Surgical tx Surgical tx Systemic tx Survival Local control Tokyo-West Tokushukai Hospital The increasing role of systemic treatment, we can consider less invasive surgical procedures.

9 Breast Surgical Oncology in an Era of Systemic Therapy Tokyo-West Tokushukai Hospital

10 Breast Surgical Oncology in an Era of Systemic Therapy Tokyo-West Tokushukai Hospital

11 Recent Advances in Breast Surgical Oncology in an Era of Systemic Therapy -saving the breast Tokyo-West Tokushukai Hospital

12 Harvard Breast Cosmesis Score after Breast Conserving Surgery Coral Q, et al. ASTRO

13 World Map of Average Breast Cup Size Average Breast Cup Size in the World

14 Optimal Margin Width in Breast-Conserving Surgery 2mm 5mm Tokyo-West Tokushukai Hospital

15 Breast Conserving Surgery in United States and Japan A lumpectomy cavity is maintained in US. Atlas of Surgical Oncology. Blackwell Science On the other hand, the cavity is sutured in Japan. 乳腺疾患の臨床金原出版

16 Impact of margin status on IBTR Adjuvant systemic therapy have demonstrated a favorable impact on IBTR Patients with positive margins who have favorable tumor biology, such as ER positive, remain at higher risk for IBTR than similar patients with negative margins. Tokyo-West Tokushukai Hospital Ann Surg Oncol (2014) 21:

17 Impact of margin status on IBTR Adjuvant systemic therapy have all demonstrated a favorable impact on IBTR Margin width greater than 2mm was not associated with reduced LR rates even in high risk TNBC cohort. Tokyo-West Tokushukai Hospital Ann Surg Oncol (2014) 21:

18 Optimal margin status in an Era of Systemic Therapy no ink on tumor as the standard for an adequate margin in invasive cancer in the era of systemic therapy Ann Surg Oncol (2014) 21: Tokyo-West Tokushukai Hospital

19 POSITION STATEMENT ON BREAST CANCER LUMPECTOMY MARGINS (2013) Optimal margin status in an Era of Systemic Therapy Tokyo-West Tokushukai Hospital

20 Oncoplastic Breast Surgery Tokyo-West Tokushukai Hospital

21 Oncoplastic Breast Surgery Tokyo-West Tokushukai Hospital

22 Recent Advances in Breast Surgical Oncology in an Era of Systemic Therapy -saving the axilla Tokyo-West Tokushukai Hospital

23 Sentinel Node Biopsy Tokyo-West Tokushukai Hospital 23

24 Management of Clinically Node Negative Axilla Tokyo-West Tokushukai Hospital

25 Management of Clinically Node Negative Axilla -Sentinel Node: Negative- ~0% X Axillary nodes Tokyo-West Tokushukai Hospital

26 Management of Clinically Node Negative Axilla -Sentinel Node: Negative- NSABP B-32 trial DFS OS Tokyo-West Tokushukai Hospital Lancet , 2010

27 Management of Clinically Node Negative Axilla 27.3% 30% Axillary nodes Tokyo-West Tokushukai Hospital JAMA 2011

28 Management of Clinically Node Negative Axilla 27.3% JAMA 2011 Axillary nodes Local rec. 1.6 vs 3.1% Tokyo-West Tokushukai Hospital

29 Radiation Field Design in ACOSOG Z % Tokyo-West Tokushukai Hospital J Clin Oncol 32:

30 Radiation Field Design in ACOSOG Z0011 not only the role of subsequent radiation therapy to the axilla but also systemic therapies 96% Tokyo-West Tokushukai Hospital J Clin Oncol 32:

31 Management of Clinically Node Positive Axilla Tokyo-West Tokushukai Hospital

32 Management of Clinically Node Positive Axilla Can NAC allow SNB to save the axilla by down-staging? Tokyo-West Tokushukai Hospital

33 Acceptable identification rates and false-negative rates According to a meta-analysis of 69 cohorts, 96% had successfully mapped SNs and the false-negative rate was 7.3%. Tokyo-West Tokushukai Hospital Cancer 2006; 106:4 16.

34 Management of Clinically Node Positive Axilla -SNB after Neoadjuvant Chemotherapy- The ACOSOG Z1071 (Alliance) Clinical Trial Tokyo-West Tokushukai Hospital JAMA. 2013;310(14):

35 Management of Clinically Node Positive Axilla -SNB after Neoadjuvant Chemotherapy- The ACOSOG Z1071 (Alliance) Clinical Trial SN was identified in 97% (one SN in 12%) after NAC. However, FNR was 31.5% when only one SN was resected and 12.6% when 2 or more were examined. Tokyo-West Tokushukai Hospital JAMA. 2013;310(14):

36 Management of Clinically Node Positive Axilla -SNB after Neoadjuvant Chemotherapy- The ACOSOG Z1071 (Alliance) Clinical Trial Tokyo-West Tokushukai Hospital J Clin Oncol

37 Management of Clinically Node Positive Axilla -SNB after Neoadjuvant Chemotherapy- SN was identified in 80% after NAC. FNR was 14.2%, but 24.3% when only one SN was resected. Tokyo-West Tokushukai Hospital Lancet 14,

38 Management of Clinically Node Positive Axilla -SNB after Neoadjuvant Chemotherapy- The SN FNAC (SNB following NAC) Study Tokyo-West Tokushukai Hospital J Clin Oncol 33:

39 Management of Clinically Node Positive Axilla -SNB after Neoadjuvant Chemotherapy- The SN FNAC Study SN was identified in 87.6% after NAC. FNR was 8.4% when SLNs with isolated tumor cells were considered positive using immunohistochemistry. Tokyo-West Tokushukai Hospital J Clin Oncol 33:

40 Management of Clinically Node Positive Axilla -SNB after Neoadjuvant Chemotherapy- Greater sensitivity could be achieved by examination of two or more SNs (number) or Introduction of IHC (definition). SNB may be offered after NAC, but the procedure seems less accurate (ASCO 2014). Tokyo-West Tokushukai Hospital

41 Tokyo-West Tokushukai Hospital

42 Recent Advances in Breast Surgical Oncology in an Era of Systemic Therapy -saving time Tokyo-West Tokushukai Hospital

43 Breast-Conserving Treatment EBCTCG (10,801 women in 17 randomized trials) In women with pn0 dx, RT reduced the 10-yrrisks of recurrence from 31.0% to 15.6%, and with pn+ dx, RT reduced it from 63.7% to 42.5%. Lancet 366:2087, 2005

44 20% of patients who underwent BCS did not receive WBI Although young age is an independent negative prognostic factor in local control, there was decrease in the receipt of appropriate radiation therapy. Young women may have distinct barriers to radiation because of the need to balance employment and child care. Breast Cancer Res Treat (2012) 135:

45 % omission of radiotherapy use after BCS in Japan

46 New schedule of breast irradiation Change in dose, fractionation, time (the same BED) Hypofractionated larger dose per fraction (high dose rate) Accelerated Shorter (less) time

47 Whole Breast Hypofractionation 47

48 Whole Breast Hypofractionation

49 Need whole-?: RT should be extended to the entire breast?

50 Adjuvant Radiation Therapy after Breast-conserving Surgery Change in volume: RT to a normal tissue surrounding lumpectomy cavity

51 Partial breast irradiation

52 Intraoperative RT (IORT) immature and too early in f/u to select the subset of patients with well-local control 2~3% absolute differences : within noninferiority margin ELIOT phiii 0.4% vs 4.4% (<7.5%) (5 yrs local rec. risk) TARGIT-A 1.3% vs 3.3% (<2.5%) (5 yrs local rec. risk) Lancet Oncol 2013; 14: Lancet Online November 11, 2013

53 Intraoperative RT (IORT) immature and too early in f/u to select the subset of patients with well-local control 3x~ higher risk for local recurrences :no radiation effect ELIOT phiii 0.4% vs 4.4% (<7.5%) (5 yrs local rec. risk) TARGIT-A 1.3% vs 3.3% (<2.5%) (5 yrs local rec. risk) Lancet Oncol 2013; 14: Lancet Online November 11, 2013

54 Intraoperative Open Cavity Implant technique (IOCI) for Brachytherapy The registration trial was initiated under the IRB in 2008.

55 Excellent

56 Good

57 Recurrence and survival rates At a median follow-up of 3.2 years, the actual rate of IBTR was 1.6% and 2.4% in PBI and WBI patients (p = 0.30). There was no significant difference in 3-year probability of DFS (98.6% vs 96.6%; p = 0.58), and OS (99.5% vs 97.8%; p = 0.17).

58 1. Potential benefits of PBI

59 1. Potential benefits of PBI Radiation dose to the LAD Nilsson JCO 2011 Int. J. Radiation Oncology Biol. Phys 2006

60 1. Potential benefits of PBI Rates of major coronary events increased linearly with the mean dose to the heart by 7.4% per gray with no apparent threshold for at least 20 years.

61 Radiation dose to the LAD Dose to LAD should be considered. PBI may reduce the risk of coronary artery disease especially in pts with lateral tumors in left breast. PBI WBI Nilsson JCO 2011 Sato, et al. J Contemp Brachytherapy 2014

62 2. Potential benefits of PBI Associations between delay in postoperative RT for breast cancer and local recurrence rates. 8 weeks after surgery after adjuvant chemotherapy Jenny Huang, et al. JCO 2003

63 3. Potential benefits of PBI Salvage mastectomy? Lumpectomy +WBI or PBI

64 Second conservative treatment for new primary cancer 5.6% 7.2% 9.6% 2nd LR rates 19.1% Dist. Mets. Five and 10-year actuarial 2nd LR rates were 5.6% and 7.2%, respectively. In case of IBTR, lumpectomy plus MCB is feasible and effective in preventing 2nd LR with an OS rate at least equivalent to those achieved with salvage mastectomy. Lumpectomy plus PBI is effective in preventing 2nd LR equivalent to those achieved with salvage mastectomy. Radiother Oncol May 3

65 Second conservative treatment for new primary cancer salvage mastectomy Mizuno Y, et al. Jpn J Breast Cancer 2011

66 66

67 Patient Selection Revised 2011 Updated 2013

68 American Society for Radiation Oncology consensus (ASTRO) guidelines Suitable Cautionary Unsuitable Factors ALL Any Any Age >=60 years years <50 years Tumor size <=2cm 2.1 3cm > 3 cm Margins -ve by at least 2mm Close < 2mm Positive Grade Any ER status Positive Negative Multicentricity Single tumor Invasive Lobular Present Multifocality Unifocal <2.0 cm Unifocal, cm Multifocal,> 3.0cm Histology IDC or favorable subtype Invasive Lobular Pure DCIS Not allowed <3 cm > 3 cm EIC (>25% DCIS) Absent <3 cm > 3 cm LVI Absent Limited or Focal Extensive Lymph nodes Negative Positive

69 Comparison of APBI and WBI in breast cancer patients with unfavorable parameters by the ASTRO guidelines Candidates of PBI as suitable patients by ASTRO guidelines Saika, et al. JMAJ 2009

70 European Association of Cardiovascular Imaging and the American Society of Echocardiography Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults Eur Heart J Cardiovasc Imaging (2013) 14 (8):

71 Impact of young age on local control after partial-breast irradiation in breast cancer Sato, et al. GBCC

72 Era of Genome Sequencing Genomic profiling has been increasingly used for risk-assessment and subsequent treatment planning for breast cancer patients. Sorlie et al. PNAS 2003

73 Molecular Subtypes affect local recurrence rates Genomic profiling can predict locoregional recurrence after BCS. Nguyen JCO 26:

74 21-Gene Recurrence Score Assay and Risk of Locoregional Recurrence RS predicted locoregional recurrence. Young patients with high RS seemed to have better clinical benefit from mastectomy than from BCT. Mamounas JCO 2010

75 ELIOT (IORT) and Intrinsic Subtypes Maluta, et al. Breast Care 2014

76 Personalized Breast Surgery in an Era of Genome Sequencing

77 Personalized Breast Surgery in an Era of Genome Sequencing Genomic profiling will be used as surgical decision-making tool in terms of surgical extent.

78 Tokyo-West Tokushukai Hospital -saving patients -

79 Thank you ONE SIZE DOES NOT FIT ALL is not only for systemic therapy but for local treatment (surgery/radiotherapy).

80 Extent of Surgery for Cancer Benign tumor Malignant tumor Tokyo-West Tokushukai Hospital

81 Future Breast Surgical Oncology in an Era of Genome Sequencing Gene-expression profiling of biopsies can predict response to neoadjuvant treatment, which can influence the extent and timing of surgery and result in less-invasive surgery. Tokyo-West Tokushukai Hospital Reimers et al. Nat. Rev. Clin. Oncol. 11, , 2014

82 Blue dye Allergic reaction (Indigo+ICG): 0.06%(2/3,377) Tokyo-West Tokushukai Hospital (S. Nakamura)

83 83

84 Eligibility Criteria Histologically documented breast cancer Stage 0, I, II (T 3.0 cm) Negative margins / Negative lymph nodes for metastasis confirmed by frozen sectioning Age 40 No prior treatment No pregnancy ECOG PS 0-2 Written informed consent Annual mammography and breast MRI were performed for the detection of locoregional recurrence.

85 Tokyo-West Tokushukai Hospital #SNs: 2.2(1-6) cf. 1.3(1-4) in RI (R Shigenaga JBCS 2009)

86 Tokyo-West Tokushukai Hospital Romeyn de Hooghe ( )

87 Advances in Systemic Therapies and Extent of surgery for Breast Cancer In terms of the impact of clinical, pathologic, and treatment factors on outcome, extensively positive margin involvement and the use of systemic therapy were most strongly associated with the risk of LR. Tokyo-West Tokushukai Hospital Catherine C. Park, et al. J Clin Oncol 18:

88 Comparison of APBI and WBI in breast cancer patients with unfavorable parameters by the ASTRO guidelines Cancer Biol Med 2014;11:

89 Partial Breast Irradiation -Intraductal Extension- Imamura Data Age > 40 = 8.32mm Ohtake Data Age > 50 = 7.77 mm William Beaumont Pathology Data All ages = 10mm in 90% of pts All > % PTs 100% ISO 75% ISO Residual disease was confined to <10 mm from edge of initial negative margin.

90 Consort diagram 375 patients underwent BCS 3 incomplete Follow-up PBI (n=252) w/ WBI (n=4) WBI (n=123) w/ RNI (n=8) w/o RNI (n=115) 5 incomplete Follow-up 249 in efficacy analysis 118 in efficacy analysis

91 Partial Breast Irradiation (PBI) Accelerated Hypofractionated Partial Breast Irradiation with High-dose rate. Accelerated Partial Breast Irradiation Partial Breast Irradiation (IntraOperative Radiation Therapy)

92 Patient demographics and tumor characteristics

93 Cases w/ IBTR after PBI

94 PBI under daily verification of the implant placement using IBU IBU Estimated direct costs of multicatheter brachytherapy ($5,168) were almost the same as those of 94 conventional whole breast irradiation ($4,068). ($1= 100)

95 Local relapse out of tumor bearing quadrant from randomized trials Trial n F/U (yrs) NSABP B-06 Uppsala- Orebro Tumor size Margins (cm) CT IBTR w/o RT (%) IBTR w/ RT (%) LR w/o RT LR w/ RT <4cm % 3.8% <2cm % - Ontario <4cm % 1.0% Milan 394 <4 <2.5cm NA + 9 <1 1.5% 0% ~4% Baglan et al., 2001

96 オンコ ( 腫瘍 ) + プラスティック ( 形成 ) Tokyo-West Tokushukai Hospital

97 Harvard Breast Cosmesis Score after Breast Conserving Surgery Coral Q, et al. ASTRO

98 Tokyo-West Tokushukai Hospital Extent of Surgery for Cancer

99 Recent Advances in Breast Surgical Oncology in an Era of Systemic Therapy Optimal local treatment should add to the effects of systemic therapy on local recurrence and mortality. Tokyo-West Tokushukai Hospital

100 Tokyo-West Tokushukai Hospital

101 American Society for Radiation Oncology consensus (ASTRO) guidelines Int J Radiation Oncol Biol Phys, pp.1179e1185, 2013

102 Sato, et al. J Tumor 2014