2ND ANNUAL SAN ANTONIO

BREAST CANCER SYMPOSIUM

REVIEW

JANUARY 28, 2012

Sponsored By:

35th Annual San Antonio Breast Cancer

Symposium: Radiation Oncology Update

Welela Tereffe, M.D., M.P.H.Department of Radiation Oncology

M. D. Anderson Cancer Center

Houston, TX

Partial breast brachytherapy is associated with inferior

effectiveness and increased toxicity compared with whole breast irradiation in older patients

Smith GL et. al. (abstract S2-1)

Partial Breast Irradiation: Patterns of Care

Breast brachytherapy after lumpectomy has emerged as a popular treatment for early breast cancer

Multiple studies document steady rise in use across the US

Ten percent of older patients are now treated with breast brachytherapy, compared with <1% a decade ago

Brachytherapy vs. Whole Breast Irradiation

Breast brachytherapy:

Delivers radiation through catheter(s)

Requires 1 week of treatment (vs. 3 to 7 weeks)

Courtesy of Dr. Grace Smith

Need For More Data Randomized trials prove effectiveness of WBI

for decreasing recurrences compared with lumpectomy alone

Randomized comparison of brachytherapy vs. WBI yet to mature

Non-randomized comparison may help ongoing treatment decisions

Courtesy of Dr. Grace Smith

• Medicare claims-based analysis• 130,535 women• Age ≥ 67 years• Incident invasive breast cancer diagnosed

between 2000 and 2007• Treated with lumpectomy• Followed by radiation treatment

• WBI • Brachytherapy

• ~75% single lumen single entry• ~25% multiplane multicatheter

Brachytherapy vs. WBI: Study Cohort

Smith GL et al, SABCS 2011

• Metastatic disease at diagnosis

• History of breast cancer

• Non-continuous/ HMO insurance coverage

• Radiation treatment type not known

• Radiation using WBI plus brachytherapy

Medicare Study Cohort: Exclusions

Smith GL et al, SABCS 2011

Patient Characteristics

Characteristic

Median follow-upMean ageWhite raceAxillary surgeryChemotherapyAxillary nodes involved

Value

3.84 yrs75 yrs92 %76 %14 %12 %

Smith GL et al, SABCS 2011

Radiation Treatment

Treatment

Brachytherapy

WBI

Total

%

6%

94%

N

7,291

123,244

130,535

Smith GL et al, SABCS 2011

Subsequent Mastectomy Risk

P < 0.001

4%

2%WBI

Brachytherapy

Courtesy of Dr. Grace Smith

Increased Risk for Mastectomy

Mastectomy Adjusted HR

2.221.00

95% CI

1.89 – 2.61–

P

<0.001

Adjusted for:Age, race, comorbidities, treatment, year diagnosis, region, SES

Brachytherapy WBI

Courtesy of Dr. Grace Smith

Subgroups: Mastectomy RiskSubgroup

4.691.00

2.061.00

95% CI

2.83 – 7.76

1.73 – 2.45

P

<0.001

<0.001

Axillary node + Brachytherapy WBI

Axillary node ─ Brachytherapy WBI

HR

No modifying effect seen with:Age, race, comorbidity, chemotherapy, year, region

Courtesy of Dr. Grace Smith

Overall Survival: No Difference

Survival

BrachytherapyWBI

Adjusted HR

0.931.00

95% CI

0.83 – 1.05–

P

0.22

Adjusted for:Age, race, comorbid, treatment, year diagnosis, region, SES

Courtesy of Dr. Grace Smith

Not surprising, since there is no survival difference for whole breast RT vs. no RT in elderly Stage I patients

Postoperative Complications at 1yr: Increased Risks for Brachytherapy

Infectious

Non-infectious

OR

1.75

1.99

95% CI

1.60 – 1.87

1.86 – 2.13

P

<0.001

<0.001

Adjusted for:Age, race, comorbid, treatment, year diagnosis, region, SES

Courtesy of Dr. Grace Smith

Brachytherapy: Excess Complications Over Time

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 180

0.5

1

1.5

2

2.5

Infectious complication

Non-infectious com-plication

Months after diagnosis

% e

xces

s ris

k

Courtesy of Dr. Grace Smith

Post-radiation Complications: 5 years

Any

Rib fracture

Fat necrosis

Breast pain

RT pneumonitis

26

4.2

9

15

0.1

Outcome Brachy (%) WBI (%) P

18

3.6

4

12

0.8

<0.001

0.03

<0.001

<0.001

<0.001

Courtesy of Dr. Grace Smith

Brachytherapy vs. WBI: Summary• Breast brachytherapy associated with

increased risks of:

• Subsequent mastectomy (failure of breast preservation)

• Acute- and long-term toxicities

• Mastectomy risk doubled, but small absolute difference in risk

Courtesy of Dr. Grace Smith

Limitations Older patients

Early generation of brachytherapy techniques No single-entry multilumen devices

Subsequent mastectomy could be due to recurrence, toxicity, or contralateral cancer Medicare claims data does not distinguish side or cause

Treatment and outcome data are claims-based

Pathology/ staging not availableCourtesy of Dr. Grace Smith

Avoid Overestimating the Importance of These Limitations

Older patients: complications ?higher but failures lower

Early generation of brachytherapy techniques: multilumen devices can decrease complications, but not necessarily failures

Subsequent mastectomy could be due to recurrence, toxicity, or contralateral cancer: mastectomy risks in this study consistent with recurrence risks in prior studies

Treatment and outcome data are claims-based: inherent limitations; still the largest cohort study to date on PBI

Pathology/staging not available: major issue. Possibility of inappropriate selection of PBI candidates

Partial breast irradiation randomized trial update:

NSABP B-39/RTOG 0413

Julian TB et. al. (abstract OT2-06-02)

PBI versus WBI: B-39/04-13DCIS or invasive cancer

Tumor ≤3cm0-3 positive nodes

Breast-conserving surgery

Whole breast irradiation(45-50Gy in 1.8-2.0Gy fx,

+/-boost)

Partial breast irradiation(physician chooses

technique)

Multi-plane Multi-catheter brachytherapy

(34Gy in 3.4Gy fx BID)

Single lumen MammoSite

(34Gy in 3.4Gy fx BID)

3D conformal external beam

RT(38.5Gy in

3.85Gy fx BID)

1° endpoint: Local control 2° endpoints: DF, OS, cosmesis, side effects

2007: closed to low risk patients (age≥50 with DCIS or invasive ER+ node-)

2011: single entry multilumen allowed (MammoSite, Contura, SAVI)

NSABP B-43/RTOG 0413Single institution data has previously shown excess toxicities

with 3D-conformal RT (3D-CRT), but this has not been demonstrated in the B-43 3D-CRT study population:

Julian TB et al, SABCS 2011

Type of Toxicity % Grade 3+Chemoradiation dermatitis <1Radiation dermatitis <1Hyperpigmentation 0Induration 2Telangiectasias <1Ulceration <1Fibrosis-cosmesis 3Fibrosis-deep connective tissue 2

NSABP B-43/RTOG 0413 Largest phase III trial on APBI

Only phase III trial testing all 3 APBI techniques Not stratified by APBI technique!

Accrual through 10/31/2011: 4023/4300

Estimated completion date: March 2013

Complete accrual critical; protocol given priority status by the Coalition of Cancer Cooperative groups

Julian TB et al, SABCS 2011

Whole breast irradiation (WBI) vs. intraoperative PBI +/- WBI:

update of the TARGIT-A trial

Vaidya JS et. al. (abstract P3-13-07)

WBRT vs. intra-op PBI +/-WBRT: TARGIT-A

n=2232Age ≥45

Invasive ductal CAUnifocal tumor

Lumpectomy planned

Intra-op PBI (surface dose ~20 Gy, dose at 1 cm ~7 Gy)

No adverse factors (85%)

Invasive lobular component OR extensive intraductal component OR or

other institution-specific adverse factors (15%)

Post-op WBI, no boost

Post-op WBI (40-56 Gy) +/- boost (10-16 Gy)

Vaidya JS at al, Lancet 2010

TARGIT-A: Patient CharacteristicsLow risk patient population:

Age 55 or older: >80%ER positive: >80%Tumor ≤ 2cm: >80%Grade 1-2: ~80%LN negative ~80%

Vaidya JS at al, Lancet 2010

TARGIT-A: 4-Year Results Number of recurrences:

Lancet 2010: 13/2322SABCS 2011: 23/2322

Kaplan-Meier 4-yr total local recurrence rate: Lancet 2010:1.08% (95% CI 0.59-1.96) IO-PBI 1.20% WBI .95% (p=NS)

SABCS 2011: 1.28%(95% CI 0.73-2.11)

TARGIT-B to open soon: Intra-op boost vs. boost after external beam RT, in women

≤45 or at high risk of local recurrenceVaidya JS at al, SABCS 2011

TARGIT-A: Patient CharacteristicsLow risk patient population:

Age 55 or older: >80%ER positive: >80%Tumor ≤ 2cm: >80%Grade 1-2: ~80%LN negative ~80%

Vaidya JS at al, Lancet 2010

Rather than administer complex and expensive treatment, can we simply omit RT

for these low risk patients?

Molecular subtype and radiation response in patients with T1 N0

breast cancer: subset analysis of a randomized

trial

Fyles A et. al. (abstract S2-2)

Omission of RT for Elderly Patients: Canadian Trial

Age ≥50Tumor ≤5cm

Node negativeBCS +/- ALND

Tamoxifen x 5 years

Tam + RT (40 Gy + 12.5 Gy boost)

Fyles, NEJM 2004

Primary endpoints: IBTR, DM, OS

Median age 68

83% T1

Omission of RT for Elderly Patients: Canadian Trial

Fyles, NEJM 2004; ASTRO 2006

5yr IBTR

8yr IBTR

Tam 7.7% 12.2%

Tam+RT 0.6% 4.1%

p<.001

No difference in DM or OS

Omission of RT for Elderly Patients: Canadian Trial

Fyles, NEJM 2004

Planned subgroup analysis: tumor ≤2cm

ER+

5yr IBTR

8yr IBTR

Tam 5.9% 15.2%

Tam+RT 0.4% 3.6%

p<0.001

Unplanned subgroup analysis: age ≥60

tumor ≤1cmER+

5yr IBTR

Tam 1.2%

Tam+RT 0%p<0.001

Small number of women Further failures expected with longer follow-up

Canadian Trial: 10-Year Results

Fyles A, SABCS 2011

10yr IBTR

p value

Tam 13.8%<.0001

Tam+RT 5.0%

Canadian Trial: Tumor Subtype and Radiation Response

Molecular subtype determined using semi-quantitative analysis of

ER HER2PR EGFR

Ki-67 CK 5/6 Analysis performed on 172/769 womenPatients classified into:

Luminal A Luminal HER2 Basal-likeLuminal B HER2-enriched Triple negative

Fyles A, SABCS 2011

Canadian Trial: Results By Molecular Subtype

Fyles A, SABCS 2011

10yr IBTR: Tam

10yr IBTR:

Tam+RTp-value

Luminal A 6.9% 4.5% .4

Luminal A + age ≥60 5.4% 6.0% .8Luminal B 23.8% 0% .012

The Luminal A subgroup represents a substantial proportion of older patients, who can be safely

spared the inconvenience and side effects of RT

Boost treatment after whole breast RT

for patients with DCIS: results from the NSABP B-24 trial

Julian TB et. al. (abstract P3-13-01)

Tamoxifen for DCIS: NSABP B-24

n=1804Stratified by age and method of detection

(MMG or PE)

Lumpectomy + RT (50 Gy, boost optional)

Lumpectomy + RT (50 Gy,boost optional)

+ Tamoxifen x5 yrs

Fisher B et al, Lancet 1999; Julian TB at al, SABCS 2011

+Margins OKExtensive calcs OK

Tumor bed boosting:Boost status and other pertinent data known for 1392 patients613/1392 received a boost85% of boosted patients received a 10 Gy boostMean follow-up time 161 months

NSABP B-24: Predictors of Boost Treatment

Patients were more likely to receive a boost if:

Younger age (≤49) p=.04Comedo necrosis p=.03Positive margins p=.007

Julian TB at al, SABCS 2011

NSABP B-24: Multivariate Analysis of IBTR

Boost treatment had no significant effect on IBTR:

Julian TB et al, SABCS 2011

No boost effect for invasive or noninvasive IBTR:

HR p-value

Age ≥50 .47 <.0001

Tamoxifen .74 .034Positive margins 1.79 <.0001Boost treatment .87 .33

HR 95% CI p-value

Invasive IBTR .86 .58-1.27 .44

Noninvasive IBTR .89 .60-1.33 .56

Ongoing randomized trial: Boost treatment

after whole breast RT for DCIS

Azria D et. al. (abstract OT2-06-01)

WBI +/-Boost for DCIS: BONBIS Trial (France)

n=1950Stratified by age, grade, margins, HT, MMG vs. PE diagnosis, center

Lumpectomy + WBI 50 Gy Lumpectomy + WBI 50 Gy + Boost 16 Gy

Azria D et al, SABCS 2011

1°endpoint: Ipsilateral breast events2° endpoints: toxicity, cosmesis, QOL

Oncotype DX® for DCIS: a prospective validation from

ECOG 5194

Solin LJ et. al. (abstract S4-6)

Omission of RT for DCIS: ECOG 5194 Observational StudyWide excision alone for “favorable” DCIS

Grade 1-2, size <2.5 cm Grade 3, size <1 cm Margins ≥3 mm Negative postoperative mammogram

Tamoxifen allowed

Hughes, JCO 2009

Omission of RT for DCIS: ECOG 5194 Outcomes

Grade 1-2580 patientsMedian tumor size 6mmMedian margin 5-10mm31% declared intention to take tamoxifen

5-yr local failure rate 6.1%

Grade 3 102 patients Median tumor size 7mm Median margin 5-10mm 30% declared intention to

take tamoxifen

5-yr local failure rate 15.3%

Hughes, JCO 2009

*Grade assignment based on local pathology review*

Development of the DCIS Score Goal: develop a genomic-based score to predict local

recurrence, regardless of tamoxifen use Gene selection: a subset of Oncotype DX RS genes

prognostic in tamoxifen treated and untreated patients

Proliferation GroupKi67

STK15Survivin

CCNB1 (cyclin B1)MYBL2

GSTM1

Reference GroupACTB

GAPDHRPLPO

GUSTFRC

Hormone Receptor GroupPR

DCIS Score evaluated as a continuous variable and in 3 prespecified risk groups (low, intermediate, high)

Unlike DS RS, the DCIS Score does not use thresholdingSolin LJ et al, SABCS 2011

DCIS Score and ECOG 5194: Study Population

Solin LJ et al, SABCS 2011

Grade (central review) 10-yr IBE rate 10-yr Invasive

IBE rate

1-2 15.4% 5.6%

3 15.1% 9.8%

Tumor tissue for DCIS Score testing available in 327/670 E5194 patients (49% of parent study)

Patients characteristcs in study group similar to that in parent study

Median f/u in this group: 8.8 years Tumor grade assessed by central review “Significant” discrepancies for local vs. central tumor grading

DCIS Score and ECOG 5194: Outcomes

Solin LJ et al, SABCS 2011

DCIS Score Risk Group N (%) 10-yr

IBE 95% CI P-value

Low (<39) 246 (75%) 12.0% 8.1%- 17.6%

.02Intermediate (39-54) 45 (14%) 24.5% 13.8%-

41.1%

High (≥55) 36 (11%) 27.3% 15.2%-45.9%

Risk-group stratified DCIS Score predicted for IBE independent of tamoxifen use

Continuous DCIS Score (adjusted for tamoxifen use) also predicted IBE: HR 2.34 per 50 units; 95% CI 1.15, 4.59; p=0.02

DCIS Score and ECOG 5194: Multivariable Models of IBE Risk

Solin LJ et al, SABCS 2011

Excluding the DCIS ScoreTumor SizePostmenopausal

Including the DCIS ScoreDCIS ScoreTumor SizePostmenopausal

P value

.01

.02

.02

.01

.02

Hazard Ratio

1.540.49

2.411.520.49

Contrast to Oncotype DX RS for invasive cancer, which predicts recurrence independent of age and tumor size

2ND ANNUAL SAN ANTONIO

BREAST CANCER SYMPOSIUM

REVIEW

JANUARY 28, 2012

Sponsored By: