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Breast ASTRO Refresher 2025 - Coggle Diagram
Breast ASTRO Refresher 2025
Objectives
Early-Stage Disease: DCIS/T1-2N0 invasive disease
Omission of radiotherapy and the integration of genomic signatures
Hypofractionation
Simultaneous integrated boost versus serial boost
De-escalation of treatment volumes
Intermediate Risk/Locally Advanced Breast Cancer:
PMRT/Regional nodal irradiation
Hypofractionation
Omission of radiotherapy for low nodal burden or ypN0
Integration of genomic signatures to RT decision-making
Particle therapy
DCIS
Classic studies: RT ↓ 50% recurrence
NSABP B-17
EORTC 10853
SweDCIS
UK/ANZ DCIS
but this population usually has favorable long term o/c
Trials that look at outcomes w/o radiation
ECOG 5194
Prospective non-randomized study of two cohorts of patients
Cohort 1 (n=561): Low- or Intermediate-grade DCIS, tumor size ≤2.5 cm
Cohort 2 (n=104): High-grade DCIS, tumor size ≤1 cm
All patient underwent surgical excision with at least 3mm margins
Radiation treatment not allowed
3 years into the study, adjuvant tamoxifen allowed (non-randomized, ~30% of patients)
Primary endpoint: Ipsilateral Breast Events (IBE) defined as local recurrence of DCIS or invasive carcinoma in the treated breast
This study is important bc pts followed long term
The risk of developing an IBE increased over time, with plateau at 15 years
1% per yr in low risk pts
1.5% higher in high risk small vol DCIS
IDC recurrence in half of recurrences
RF
Study cohort and tumor size
NOT: Age, meno status, minimum negative margin
20-year IBE: 18% cohort 1 vs. 29% cohort 2
20-year invasive IBE: 10% cohort 1 vs 15% cohort 2
Can forego RT in GOOD risk DCIS after lump
risk of LR is modest
Wright, et. al., NPJ Breast Cancer, 2024
Solin, et. al., Journal of Clinical Oncology, 2015
Randomized confirmation of ECOG 5194
RTOG 9804
Low risk def. same as 5194
RCT
Lumpectomy
Low or intermediate nuclear grade histology (G1-2)
Unifocal lesion, ≤ 2.5 cm on pathology or mammogram
Surgical margin width of 3 mm
Radiation Therapy
50 Gy in 25 fractions or 50.4 Gy in 28 fractions
2001 amendment allowed 42.5 Gy in 16 fractions
Tamoxifen optional
Median follow-up: 14 years
Any IBR₁₅: 15% Obs versus 7% RT
Invasive IBR15: 10% Obs versus 5% RT
Curves remain separated, low incidence in 1st 10 yrs.
Tamoxifen use was the only variable in addition to RT significantly associated with a reduction in IBR (p=.0047)
Is there a better way to find those who benefit from RT? Stratify risk?
Oncotype DCIS
Goal: Assess risk of developing an IBE in w DCIS treated with surgical excision alone
Oncotype DX breast cancer assay: DCIS Score calculated from 7 cancer-related genes and 5 reference genes
327 patients with tissue (ECOG E5194 trial)
Low- or intermediate-grade DCIS, size ≤ 2.5 cm or high-grade DCIS, size ≤ 1 cm
Sorted into risk groups based on assay score: low, intermediate, high
IBE 10Yr
Low: 11%
Intermediate: 27%
High: 26%
in addition to other path RF, DCIS is a good estimator of recurrence in GOOD risk DCIS
Other risk cohorts?
Hi/int Significantly associated w/ LR, HR 1.75
There is still benefit of RT in low risk
Solin, et. al., JNCI, 2013
DCISionRT
Risk and value add of RT (predictive)
Goal: Avg 10-year ipsilateral breast event rate of 10% and an IBC risk of 6% or less
Risk threshold:
Low Risk Group DS ≤ 3
Elevated Risk Group: DS > 3
Results: DCISionRT score assd w/ invasive breast cancer risk and any IBE
The difference in 10-year recurrence risk between
low-risk patients treated with and without RT was 1%
Elevated risk group received significant benefit from RT (
difference of 6% for IBC and 12% for IBE
)
not yet validated in RCT, but validated in SweDCIS retrospectively
Observation alone
COMET
Inclusion
Age ≥40
Grade 1-2 ER+ and/or PR+ DCIS
Any size
Guideline concordant: Sx w/ w/o RT
active monitoring; 6 mo ipsi mammo & 12 mo contra mammo
Surgery in monitoring group prompted by disease progression on imaging necessitating core biopsy+ invasive cancer
median follow-up of 37 months
2-year rate of invasive cancer (ITT) was 4% active monitoring versus 6% guideline concordant care (non-inferior)
only 52% randomized to guideline concordant care had received surgery by 6 months.
Note this is not PRIME II, this is just Low risk. Not yet SoC
Hwang, et. al., JAMA, 2025
2018 ASTRO Executive Summary Guidelines on WBI (DCIS or IDC)
Hfx WBI may be used as an alternative to conventional fractionation in pts w/ DCIS
A tumor bed boost may be used for pts w/ DCIS who meet any of the following criteria:
Age ≤ 50 yr,
High grade,
Close (<2mm) or SM+
Omission of boost suggested
Age >70 yr
HR+ w/ low or int grade
wide neg margin (>2mm)
Smith et al. PRO 2018:8:145-152
Risk Factors for LR in DCIS
4 prognostic factors associated with LR:
Age <50
Size >2.0cm
Grade 3
SM+ or close <2mm margin
Additional risk factors
Palpable/ bloody discharge
Comedo, Solid types of DCIS
Black race
ER- and/or PR-
SSO/ASTRO Surgical Margin Guidelines for DCIS
≥ 2mm margin is considered SM-
Hypofx and Boost
BIG 3-07/TROG 07.01
Chua, et. al., The Lancet, 2022
RCT : 1608 women w/ completely excised
non-low-risk DCIS
comparing RT to
Hfx AND boost to no boost
(4 arms)
1º EP: Time to LR at 5 years
Non-low risk
defined as >=1 of the following:
<50 years
palpable tumor
size >=15 mm,
multifocal disease
nuclear grade 2 or 3
central necrosis
comedo-histology
SM- <1 cm
Median follow-up: 6.6 years
No difference in 5-year FFLR between Hfx arms (both 95%)
Significant improvement in 5-year FFLR: 93% no boost versus 97% boost group
All subgroups benefited from a boost
Confirmatory Study
DBCG HYPO
Non-inferiority
study of breast induration
when comparing conventional to moderately Hfx breast RT
Eligibility
40 years
BCS for pT1-2N0-1mi IDC or DCIS
Stratified by CHT, breast size, and boost
Conventional RT (n=937)
50 Gy in 25 daily fractions
Hfx RT (n=917)
40 Gy in 15 daily fractions
Primary endpoint: 3-year grade 2-3 breast induration
Median follow-up: 7 years
3-year rate of grade 2-3 induration not diff:
50Gy: 12%
40Gy: 9%
Patient overall satisfaction w/ cosmetic o/c favored the 40Gy arm
Low morbidity
for patients treated w/ systemic therapy, boost, and w/ larger breasts
Conventional RT for Early stage Breast Cancer is no longer SoC
TAM use in DCIS (ASTRO R 2022)
NSABP B-17 and NSABP B-24
no requirement for HR+
RT has bigger LR effect
role for TAM in reducing contralat BC
B-14 saw no TAM benefit in ER-
Hormone Therapy and Radiation for DCIS
If prevention of IBTR is the goal, TAM can't replace RT after BCS
RT has a significantly greater impact on reducing ipsilateral breast events than tamoxifen
Tamoxifen may further decrease LR risk after BCS w/ RT and significantly reduces contralateral breast events
In
postmenopausal women < 60 yr of age
, anastrozole may be more effective than tamoxifen (IBIS-II DCIS
(NS)
; B-35 (
p=0.02
))
Early Stage IDC
Old studies show sizable (↓ 2/3) reduction in recurrence w/ RT
NSABP B-06
Like DCIS, can we find people who dont need RT?
CALGB 9343
RCT: RT + ET versus ET alone after BCS
patients ≥70
clinical stage I ER+ breast cancer
cN0 axilla
Lumpectomy
RT vs RT and TAM
Median follow-up: 13 years
Freedom from LRR10:
ET + RT:
98%
(95% CI, 96%-99%)
ET alone:
90%
(95% CI, 85%-93%)
only 8% benefit at 13y
No difference in mastectomy rate, DM, or OS
OS10: ET + RT 67% versus ET alone 66%
Reduce the age criteria.
PRIME II
Age 65 or older
HR+
N0
T1 / T2 primary breast cancer up to ≤3 cm
(grade 3 histology or LVI permitted, not both)
BCS with clear excision margins (≥1mm)
Negative pathological axillary staging
Adjuvant ET
RCT: RT vs no RT w/ ET
Median follow-up: 9.1 years
10-year cumulative incidence of LR:
10% in the no-radiotherapy group
1% in the RT group
No difference in DM as first event, OS, regional recurrence or breast cancer-specific survival between groups
If pts meet the criteria, they can omit RT
Tumor Biology driven stratification: Omit RT
LUMINA
Women ≥55 years
Undergone BCS for
grade 1-2 T1N0 BC; ≥ 1mm
margins of excision
Luminal A subtype (
defined as: ER+ ≥ 1%, PR+ >20%, HER2- and Ki67 ≤ 13%)
Treated with adjuvant ET
N=500
Median f/u = 5 yrs
Median age = 67
Median tumor size = 1.1 cm
LR= 2%
Genomic driven stratification: Omit RT
IDEA
younger postmen pts, w/o RT, w/ genomic assay
single arm trial
if 5 yrs ET
N=200 (n=186, at 56 months follow-up)
pT1N0
unifocal IDCw/
margins ≥2 mm after BCS
ER+ and PR+
HER2-
Oncotype DX 21-gene recurrence score ≤18
Overall and breast cancer-specific survival rates at 5 years: 100%
5-year freedom from any recurrence: 99%
Crude rates of LR
50-59 y/o: 3% (2/60)
60-69 y/o: 4% (5/140)
Conclusion: A very low risk of recurrence can be achieved when using a genomic assay in combination w/ classic clinical and biologic features for treatment selection.
Jagsi, et. al., JCO, 2023
Ongoing Trials of Omission in Low-Risk Breast Cancer
DEBRA (BR007)
Target (N=): 1670
Age (y): 50-70
Eligibility: RS <18
1º Endpoint: 10-year IBTR
PRECISION
Target (N=): 1380
Age (y): 50-75
Eligibility: PAM50 low risk
1º Endpoint: 5-year LR
HERO
Target (N=): 1300
Age (y): ≥ 40
Eligibility: HER2+
1º Endpoint: 10.5-year recurrence-free interval
EXPERT
Target (N=): 1167
Age (y): ≥50
Eligibility: PAM50 low risk
1º Endpoint: 10-year LR
EUROPA*
Target (N=): 926
Age (y): >70
Eligibility: T1N0 Luminal A
1º Endpoint: 5-year IBTR and QoL
QoL improving: RT vs ET
EUROPA, interim analysis
Non-inferiority, phase 3, randomized controlled trial of RT alone versus ET alone after BCS for patients ≥70 with clinical stage I luminal A-like (ER+/HER2-, KI-67≤20%) breast cancer
(sample size, n=926)
pT1a-T1bN0, any grade or pT1cN0 grade 1-2
Stratification by age and health status
Primary endpoints:
Change in Health-Related QoL (GHS[Global health status], EORTC QLQ-C30) at 24 months
LR at 5 years
Radiotherapy (n=104)
WBI or
PBI, w/ preference for 5 fraction schedule
Endocrine therapy (n=103)
AI or Tamoxifen x 5-10 years
GHS declined more in the ET group at 2 yrs.
* RT appears to be assd w/ improved QoL compared to ET alone
RT arm: 85% PBI/15% WBI
Fewer patients in ET group completed QOL assessments and planned study visits, more
ET patients discontinued treatment due to adverse events
and more withdrew consent upon randomization
awaiting LR o/c
Hypofx
now the SoC
Canadian OCOG
Whelan et al NEJM 2010
RCT comparing a 5-week standard WBI to a
Hfx 3-week WBI.
Eligibility:
pT1-T2N0 IDC w/ lumpectomy w/ SM-
25% age <50
31% T2
26% ER-
19% grade 3
11% chemo
LR10
: 7% 50Gy versus 6% 40Gy
(Abs diff 1%; 95% CI, -3 to 4)
No difference in cosmesis
"Good" or "excellent": 71% versus 70%**
(Abs diff, 2%; 95% CI, -7 to 10)
No difference in DFS10 or OS10
START B
RCT : 5-week standard fractionation WBI/chest wall RT vs
Hfx 3-week WBI/chest wall RT*
Eligibility
pT1-3a pN0-1 M0
SM- ≥1mm
No immediate surgical reconstruction
LR10 not diff
Breast shrinkage, telangiectasia, edema, sig less in the 40Gy group.
Even shorter HFX
UK FAST :camera_with_flash:
Multicenter, phase III RCT of assessing normal tissue effects of WBI for early-stage IDC delivered:
1º EP: Changes in
photographic breast appearance at baseline
, 2, and 5 years after RT
Secondary endpoints: IBTR, new primary disease, physician assessments of normal tissue effects (NTE)
age 50,
tumor size < 3cm
SM-
N0
50 Gy
30 Gy
28.5 Gy
M follow-up: 9.9 years
5 years,
80% of patients had no change in photographic appearance
Significantly higher rates of change for 30 Gy schedule versus 50 Gy (p=0.019), but
comparable changes in appearance between 28.5 Gy and 50 Gy (p=0.686)
At 10 years, no differences in LR between arms (
all <2%
)
Normal tumor effects 30 Gy >> 50 Gy and between 30 Gy >> 28.5 Gy (p=0.008)
Any NTE was not significantly different between 50Gy and 28.5Gy (p=0.248), though rate of moderate to marked breast induration was higher in 28.5Gy arm
FAST-Forward
Multicenter, phase III RCT evaluating the efficacy and safety
4096 patients diagnosed
w/ IDC
pT0-3, N0-1, M0
40 Gy total dose across 15 fractions over 3 weeks
27 Gy total dose across 5 fractions (5.4 Gy) daily over 1 week
26 Gy total dose across 5 fractions (5.2 Gy) daily over 1 week
1º EP: LR
(assuming a 2% 5-year incidence for 40 Gy, non-inferiority was predefined as ≤2% excess LR rate for five-fraction schedules)
Secondary endpoints: Late NTEs as assessed by clinicians, patients, and from photographs; disease-related and survival o/c
m f/u: 72 months
Median age: 61 years
Median tumor size: 1.6 cm
Patients stratified by risk group
Low risk (≥50, grade 1/2) (62%)
High risk (≤50 or grade 3) (38%)
5-year CI LR not diff:
40Gy - 2%
27Gy - 2%
26Gy - 1%
Significantly higher risk of moderate/marked breast shrinkage, distortion, induration, and edema for 27Gy vs. 40Gy
Statistically significant, but small absolute differences in moderate/marked normal breast induration and edema for 26Gy vs. 40Gy
(<1% in each, large N, clinically insig)
ASTRO Consensus Guidelines 2018
"For women receiving WBI w/ or w/o inclusion of the low axilla, the preferred dose-fractionation scheme is moderate
Hfx WBI to a dose of 4000 cGy in 15 fractions or 4250 cGy in 16 fractions
."
Strong recommendation for moderate Hfx regardless of tumor grade, laterality, breast size, or use of concurrent ET/Trastuzumab
Expect updates for UHFx
BIG 03-07 and DBCG HYPO provide level 1 evidence for DCIS MHFx w/ boost
NCCN:
28.5Gy/5 for >50 with no boost indications
26Gy/5 also possible
Ultrahypofractionation Considerations
Per FAST:
Breast PTV Dmax ≤ 107%
Breast PTV 105% ≤ 5%
Per Fast Forward:
Ipsilateral lung V8 Gy < 15%
Heart V1.5 Gy < 30% and V7 Gy < 5%
Breast PTV 105% < 5%, PTV 107% < 2%, Dmax < 110%
Boost
Historical trials show LC benefit with serial lumpectomy boost after WBI.
All pts benefit, young pts benefit more
Long term data, Lyon and EORTC
How best to deliver Boost?
IMPORT HIGH: MHFx with SIB vs Seq
Phase III, non-inferiority, open-label, RCT to test
SIB against sequential boost
2436 women w/ pT1–3pN0–3aM0 IDC treated w/ breast conserving surgery and adjuvant radiation therapy
Testing RT delivered over either 15 days versus 23 days
Control/Sequential boost (n = 816)
40 Gy in 15 fractions WBI
16 Gy in 8 fractions sequential tumor-bed boost
Test Group 1 (n = 813)
36 Gy in 15 fractions WBI
40 Gy in 15 fractions to the partial breast
48 Gy in 15 fractions w/ SIB to the tumor-bed volume
Test Group 2 (n = 807)
36 Gy in 15 fractions WBI
40 Gy in 15 fractions to the partial breast
53 Gy in 15 fractions w/ SIB to the tumor-bed volume
1º EP: IBTR
m f/u 74 months:
5-year IBTR incidence 2% control, 2% test group 1, 3% test group 2
Non-inferiority IBTR achieved absolute terms according to prespecified difference 3% test group 1 versus control, not test group 2
5-year incidence clinician-reported moderate or marked breast induration 12% control versus 11% test group 1 (p=0.40) versus 16% test group 2 (p=0.015)
Worse in Group 2 (highest SIB)
5-year patient-reported moderate or marked breast hardness or firmness significantly lower test group 1 versus control (p=0.001)
equivalence in SIB, not to exceed 48Gy
Same question: SIB MHFx?
RTOG 1005
RCT of stage 0-II breast cancer w/ elevated risk of LR following lumpectomy necessitating a boost
Stratified by:
Tumor grade (3 vs. 1-2)
Age <50 vs ≥50
Receipt of adjuvant CHT
ER status
Arm 1 Control (n=1,124)
WBI (42.7-50Gy in 16-25 days)
Sequential boost (12-14Gy in 6-7 days)
Arm 2 SIB (n=1,138)
WBI (40Gy in 15 days)
Concurrent boost to the surgical site (48Gy in 15 days)
1º EP: LR
m f/u: 7 years
Median age 55 years, 34% Stage II, 52% grade 3, 30% ER-, 17% close/SM-
5 & 7-year LR
:
2/2% control versus 2/3%
SIB arm
3-week treatment met non-inferiority criteria for IBR: p = 0.039
3-year physician rated excellent/good cosmesis by arm: 86% for control vs 84% SIB, p=0.61
SIB is very appropriate, up to 48 Gy
Vicini, ASTRO, 2022
APBI: Deescalating Volume
Intraop
ELIOT (electron intraoperative radiotherapy)
RCT comparing WBI to intraoperative electrons 21Gy/1fx
Eligibility:
Women 48-75 years
clinical ≤2.5cm unicentric IDC
Clinically N0
WBI (n=654)
Post-operative WBI:
50Gy / 25 fractions + 10Gy boost
Intraoperative partial breast irradiation (n=651)
21Gy intraoperative RT w/ electrons (ELIOT) in a single dose to the tumor bed
1º EP: Rate of IBTR (LR)
m f/u: 12.4 years
LR rate:
WBI 10/15-year: 1/2%
ELIOT 10/15-year: 8/13%
OS: No diff between arms (HR 1.03, p=0.85)
Way worse LR (11%), no OS diff
Similar Intraop: 21Gy/1fx
TARGIT-A Trial (Vaidya et. al., The Lancet, 2014)
RCT, non-inferiority trial
Compares single-dose TARGIT
vs
Fractionated EBRT for breast cancer
Eligibility:
Women ≥ 45 years
IDC
1º EP: LR
Prespecified non-inferiority margin of 3% at 5 years
EBRT (n=1730) conventional
TARGIT (n=1721): 20–45 min to the tumor bed
Surface of the tumor bed typically receives 20 Gy that attenuates to 5–7 Gy at 1 cm depth
Met non-inf for LR (prespecified -12% control, lol), however...
At 5-year m f/u, when all patients were analyzed together
Overall, breast cancer mortality ~same for TARGIT and EBRT
The risk-adapted design of the TARGIT group must be followed
i.e. when higher risk factors are found postoperatively, EBRT should be added
EBRT QD
IMPORT LOW: 40/15
RCT phase III non-inferiority trial evaluating partial-breast versus WBI in women at lower-than-average risk of LR
Eligibility:
≥ 50 years s/p breast-conserving surgery w/
≥ 2 mm SM-
Grade 1-3 IDC
p tumor size < 3 cm
N0-1
Control (WBI) (n=674)
40 Gy WBI
Reduced-Dose Group (n=673)
36 Gy WBI and
40 Gy to the partial breast
Partial Breast Group (n=669)
40 Gy to the partial breast in 15 daily treatment fractions
1º EP: LR
m f/u: 72 months
5-year abs differences in LR vs. control group:
Reduced-dose: -1%
PBI group: 0%
Non-inferiority can be claimed for both reduced-dose and PBI
PRO favored the PBI (IRR, 0.77; P < .001)
and reduced-dose (IRR, 0.83; P < .001) vs. WBI group
EBRT: DCIS or IDC
RAPID: Canadian MHFx vs 38.5Gy/10 BID
RCT, non-inferiority trial comparing external beam APBI vs. WBI
Eligibility:
≥40 years
DCIS or IDC ≤ 3 cm in greatest diameter
SM-
N0
WBI (n = 1065)
42.5Gy in 16 fractions once per day over 21 days, or 50Gy in 25 fractions once per day over 35 days
APBI (n = 1080)
38.5 Gy in 10 fractions delivered BID over 5-8 days
1º EP: LR (IBTR)
LR, acute tox were similar, Late Tox worse (~16%)
m f/u: 9 years
8-year rates LR: APBI: 3% vs WBI: 3%
Acute RT toxicity (grade ≥2, within 3 months of RT) less frequent among APBI patients (p<0.0001)
Difference in late adverse cosmesis with APBI (Fair + Poor):
3 years 11%
5 years 17%
7 years 18%
Cosmesis is a big concern with APBI
EBRT: More attempts
NSABP B-39: 50Gy vs 38.5Gy BID
WBI (n = 2039)
25 daily fx of 50 Gy
over 5 weeks (+/- boost to tumor bed)
APBI (n = 2093)
34 Gy of brachytherapy
or
38.5 Gy EBRT in 10 fx,
over 5 days within an 8-day period
Eligibility:
Women >18 years
Early-stage breast cancer: 0, I, or II
no evidence of distant metastases
but up to 3 axillary nodes positive (tumor size ≤3 cm)
SM-
1º EP: IDC and non-invasive LR as a first recurrence
m f/u: 10 years
10-year cumulative incidence of LR:
WBI: 4%
APBI: 5%
pretty much the same
Deaths from recurring breast cancer:
WBI: 44 (2%) of 2039 patients
APBI: 49 (2%) of 2093 patients
APBI did not meet criteria for equivalence in controlling LR, however, w/ an abs difference <1%,
APBI is an acceptable alternative for eligible patients
Intracavitary?:: unplanned SGA showed worse LR
When excluded, EBRT APBI had same LR as WBI
tumor control isn't compromised by PBI
Cosmesis: NS
Photographic assessments were the same in non CHT cohort.
Probably need to optimize dose fx for cosmeses. BID
ACCEL: Optimizing Dose and Fx for Cosmesis
Multicenter, single-arm, phase II prospective cohort study
Eligibility:
Women 50 yr or older w/ ≤3cm ER+/HER2- IDC or DCIS after BCS
All receive 27 Gy in 5 daily fx of APBI
1º EP: Non-inferiority of 2-yr cosmesis using the RAPID WBI arm as the control arm
m f/u: 2 yr
Cosmesis w/ ACCEL trial regimen was deemed non-inferior to WBI arm of RAPID trial; 88% RAPID WBI vs. 100% ACCEL trial
ASTRO consensus guidelines
APBI strong rec
Grade 1-2 disease; low-int nuc grade
ER+ histology
Age ≥40 yr
Tumor size ≤2 cm (DCIS or IDC)
conditional rec for some risk factors
T2 (or DCIS < 3cm)
Grade 3
ER-
High grade DCIS
NCCN guidelines suggest FLORENCE/IMPORT LOW for APBI
2022 ESTRO Guidelines adopted 6 Gy in 5 fx for APBI extrapolating from Fast Forward
ACCEL trial for a daily 5 fx regimen, it is reasonable to conclude that 26-27 Gy in 5 daily fx is also an appropriate approach to APBI
ABS consensus statement
Lobular ok
ER- ok
2mm margin
N0
EBRT EOD
FLORENCE
Meattini et al. J Clin Oncol, 2020
WBI (n = 260): 50 Gy in 25 fx w/ a tumor bed boost
APBI (n = 260): 30 Gy in 5 fx EOD
Eligibility:
age > 40 yr suitable for BCS
Early breast cancer,
tumor size ≤2.5 cm
5mm+ SM-
1º EP: 5-yr difference in IBTR
Secondary endpoints: LRR, DM, and CBC rates, BCSS, and OS, acute/late treatment-related toxicity, and cosmetic o/c.
m f/u: 11 yr
10-yr cumulative incidence of LR:
WBI:
3% (
n=6)
APBI:
4%
(n=9)
No diff in OS or BCSS
APBI arm showed significantly improved treatment-related AEs in both the acute (P = .0001) and late (P = .0001)
Physician and patient-rated
cosmesis both significantly favored the APBI arm
Dose and fx is really at the heart of cosmoses concerns with RAPID
Deescalate SLNB
APBI required SLNB
SOUND
SLN biopsy vs. No axillary surgery (1:1 RCT)
2012-2017
n=1463
cT1N0 IDC
14% N+
9% macro
5% micro
88% ER+/ grade 3 ~18%
o/c 5yr:
DDFS 98% SLNB (2% LR)
DDFS 98% No surgery (2% LR)
INSEMA
SLN biopsy vs. no axillary surgery (4:1)
2015-2019
n=5502 pts
cT1-2N0
90% T1
15% N+
12% macro
4% micro
99% HER2-
grade 3 ~4%
o/c iDFS 5yr:
92% SLNB (0% LR)
92% No surgery (1% LR)
Among patients w/ early-stage IDC the field is moving toward less RT utilizing shorter, increasingly Hfx, and less expensive courses of therapy and smaller treatment volumes
Before utilizing genomic signatures to justify omitting RT or prior to utilizing APBI and ultrahypofractionation consider individualized risk, particularly where
specific populations were not well represented in the above studies (e.g. young age, large breast size, baseline unfavorable cosmesis, no axillary evaluation)
, and employ shared decision-making
Intermediate and LA Breast cancer
PMRT Early Trials: Establishing the benefit of RT in LA Breast Cancer
British Columbia Study
1979-1986
318 Premenopausal women
mod RadMast (ALND) -> pN+
Median 11 LN’s removed
Adjuvant CMF x 9c, q3w, (+/- ovarian RT)
Ipsilateral CW, SCV, axilla, and bilateral IMN RT 37.5Gy in 16 - 2.34Gy fx w/ Co-60 (between cycle 4-5 CMF)
RT cobalt is outdated, HFx is weird, CHT is outdated
NO RT
↓ Isolated LR20 : 26% → 10%
↑ BCSS20: 38% → 53%
↑ OS20: 37% → 47%
OS improved among both patients with 1-3 N+ and those with 4 or more N+
Danish 82b and c Studies: b (postmeno), c (premenopausal)
1982-1990
Comprehensive RT: 50Gy in 25 – 2.0Gy fx vs. NO RT
82b: 1375 post-menopausal, <70 yr (adjuvant Tamoxifen x 1 yr)
82c: 1708 premenopausal (adjuvant CMF x 8c, q4w)
“High risk”
tumor ≥5cm
N+
invasion of skin or fascia
Total mastectomy + ALND
median 7 lymph nodes removed
↓ Isolated LRR10 : 26% → 5%
↑ OS10 : 45% → 54%
↓
Isolated LRR10 : 29% → 4%
↑
OS10 : 36% → 45%
LR and OS10 benefit, comparable to British Columbia
(~10%)
Frequently Cited Limitations
Outdated systemic therapy, both in type and timing relative to PMRT
Median number of nodes in the Danish studies did not meet criteria for a completion axillary dissection, ? inappropriate downstaging (>=10 is NCCN std)
LR in “no RT” arms considered high, even for the era
1-3 nodes: about 13% LRF
4+ nodes: 25% LRF (consistent with BC and Danish)
So in 1-3 nodes, is PMRT needed?
Danish Study Re-Imagined:
Retrospective evaluation of 1152 N+ patients with > 8 LN removed in Danish studies 82b & 82c
9% survival advantage similar between patients in 1-3 N+ group and >4 N+ group
EBCTCG MA 2014
N0 patients do not benefit from PMRT
1-3 N+
and ≥4N+
patients demonstrated a LR and mortality benefit w/ PMRT
3401/8135 = 42% patients were enrolled in BC or Danish RCTs
Conclusions are only as good as the studies included
limits of the studies carry on in MA
RNI
Trying to answer the question about Low N+ burden PMRT: CW RT
SUPREMO
RCT : PMRT vs. none
Stage II IDC w/ 1
1-3N+ following mastectomy + axillary node clearance
pT1-2N1 (inclusive of micrometastases)
pT2N0 if grade 3 and/or LVI
pT3N0
ypT0-2N0-1 or ypT3N0
1º EP: OS₁₀
CW irradiation alone
Nodal irradiation left to physician decision
75% received ALND
No longer considered SoC
25% were pN0
40% had only 1 node
this was especially a low risk group
HR+ HER2 negative was the majority (few TNBC)
OS₁₀: No diff
CW recurrences: only modest diff (prob clinically insignificant)
LRR: Modest diff in N+
Pts who meet SUPREMO should not be offered CW radiation
Ok but does this mean Nodal RT should be performed?
EORTC 22922
Eligibility
Unilateral histologically confirmed stage I-III IDC
Centrally or medially located primary tumor (44%) irrespective of axillary involvement
Externally located tumor with axillary involvement (56%)
s/p mastectomy (25%) or BCS (75%) and axillary dissection
Control Group (n=2002)
WBI or chest wall RT alone
(50Gy in 25 fx)
Nodal-Irradiation Group (n=2002)
WBI or chest wall RT plus regional nodal irradiation (medial SCV, IMN)
(50 Gy in 25 fx)
1º EP: OS
Secondary endpoints: DFS, survival free from DM, and death from breast cancer
Majority clinical stage II patients w/ pT1-2 and pN0-N1 disease
At 15-yr f/u, no significant improvement in OS or DFS, but there
was an improvement in:
LR (25% vs. 27%; HR 0.87, p=0.024) w/ RNI
Breast cancer mortality (16% vs. 20%; HR 0.81, p=0.0055) w/ RNI
NCIC-CTG MA.20
Eligibility:
Women w/ N+ or high-risk N0 IDC who were treated w/ BCS, ALND, and adjuvant systemic therapy
High risk features:
Tumor measuring ≥5 cm or
≥2 cm
w/ at least one of the following:
grade 3
ER-
or LVI
Control Group (n=916)
WBI alone
Nodal-Irradiation Group (n=916)
WBI plus regional nodal irradiation (level III axilla, SCV, IMN)
1º EP: OS
Secondary endpoints: DFS, isolated locoregional DFS, and distant DFS
Majority clinical stage II patients w/ pT1-2, but majority were N1, w/ only 1 or 2 positive lymph nodes
Most patients received modern adjuvant CHT
m f/u: 10 yr
OS at 10 yr: 83% RNI vs. 82% control (p = 0.38)
Significant improvements in DFS, local regional DFS, and DM
No diff in late effects including cardiac toxicity or pneumonitis
Strengthens support of RNI
Whelan, et. al., NEJM, 2015
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How should IMN be managed?
What about cardiac toxicity?
KROG 08-06
Multicenter, phase III RCT
735 women
axillary N+ IDC after ALND
All received WBI/CW and SCV RT
373 received
no IMN-RT
362 received
IMN-RT to 1st 3 IC spaces
m f/u of 8.4 yr
1º EP: 7-yr DFS
Secondary EPs: rates of OS, breast cancer mortality, LR, regional recurrence, DM-free survival, acute/late AEs
m f/u: 8 yr
2% improvement in 7-yr DFS in IMN vs. non-IMN-RT cohort (NS, p=0.22)
SGA demonstrated significant DFS improvements in mediocentral tumors
BCSM7: 10% vs. 5%
(HR=0.41, p=0.04)
DMFS7: 82% vs. 92%
(HR=0.44, p=0.01)
OS7: 89% vs. 93%
(HR=0.51, p=0.08) [trend]
Greater benefit in ER- disease
Comparable
rates of AEs in both groups, including
cardiac toxicity
(1% vs 2%)
Radiation pneumonitis higher in IMN-RT group (6% vs 3%, p=0.06)
50% were N1
remainder N2+
so study is "enriched" for greater dz burden
N+ with central or medially located tumors might need IMN
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RNI Recommendations
RNI improves
DFS and breast cancer mortality
in ≥pN+ patients treated with modern systemic therapy
w/o an associated increase in cardiopulmonary tox
when the IMN’s are treated
IMN RT
: greater survival benefit in pts with
positive axillary nodes and central or inner quadrant t
umors and/or those with ER- subtype
Soc is no longer ALND, so true extent of nodal dz is not clear in surgical staging
ALND vs SLNB
Breast Cancer Axillary Management Trials
omission of ALND in cN0
pN+(sn)
AMAROS/OTOASAR, SENOMAC demonstrate Ax RT did not have worse o/c to ALND
AMAROS and OTOASAR has ↓Arm and shoulder morbidity w/ RT
Z0011
Dates: 1999-2004
N=: 813
Eligibility: cT1-2N0
SLN+: 93%
SLNB: 55% macro, 45% micro
Addt’l N+: 27%
RNI: N
LRF/Axillary Failure: 5y: 4% ALND vs. 3% SLN
AMAROS
Dates: 2001-2010
N=: 4806
Eligibility: cT1-2N0
SLN+: 30%
SLNB: 59% macro, 29% micro
Addt’l N+: 33%
RNI: Y
LRF/Axillary Failure: 10yr: 1% ALND vs. 2% RT
Lymphedema was observed and treated significantly more often after ALND than after AxRT at every measured time point
44% ALND
29% ART
No diff between any of the selected scales (arm symptoms, pain, or body image) at 1, 3, and 5 yr
OTOASAR
Dates: 2002-2009
N=: 2106
Eligibility: cT≤3cmN0
SLN+: 25%
SLNB: 60% macro, 34% micro
Addt’l N+: 39%
RNI: Y
LRF/Axillary Failure: 8yr: 2% ALND vs. 2% RT
1-yr rates of clinical lymphedema, paresthesia, swelling, arm pain, and shoulder mobility were higher in the cALND group
15% ALND
5% RNI
No significant or clinically relevant diff in QoL were noted between the two groups
SENOMAC
Dates: 2015-2021
N=: 2540
Eligibility: cT1-3N0
SLN+: 100%
SLNB: 85% 1N, 15% 2N
Addt’l N+: 35%
RNI: Y
LRF/Axillary Failure: 5y: 1% ALND vs. 1% RT
NCCN Guidelines RNI PMRT
1–3 positive axillary nodes → Strongly consider PMRT to chest wall + comprehensive RNI (including any portion of the undissected axilla at risk).
RNI BCS SLNB
BCS w/ >1-2 SLN+ → can/should get RNI
must meet all crit
cT1–T3, N0
No preoperative CHT
WBI planned
this is from SUPREMO
IBCSG-23-01
N = 931
Eligibility: 1-2 micromets, T1-2, sp SLNB
RNI: N, WBI
LRF/DFS10(76%)/OS: NS
Lymphedema 13% ALND vs 4% obs
Obs noninf for ALND
RNI HFx
briefly done in START B and BC trial
Chinese NCC Trial: 1st HFx RNI/PMRT w/o Recon
RCT phase III non-inferiority study comparing a 3-week HFx PMRT vs. a 5-week conventional RT
Eligibility
pts aged 18–75 yr
Undergone mastectomy
pT3-4 and/or pN2
Conventional Fractionated RT (n=414)
50 Gy in 25 fx over 5 weeks
Hfx RT (n=406)
43.5 Gy in 15 fx
over 3 weeks (CW, SCV, level III)
no IMN, no I/II axilla bc they had dissection
RT to CW was electron based
1º EP: 5-year LR (5% margin was used to establish non-inferiority)
m f/u: 59 months
5-yr cumulative incidence of LR
not diff (good!)
8% in the Hfx RT group
8% in the conventionally fractionated RT group
No significant diff between the groups in acute and late toxicities
1% had G3 LE
20% had G1/2 LE
Hfx RT group had
↓ 5%!
acute grade 3 skin toxicity
(3% 3-weeks vs 8% 5-weeks; p<0.0001)
Still fears of ↑ HFx complication rate with Mastectomy w/ Reconstruction
FABREC
m f/u: 40 months
RT vs MHFx (16fx)
Immediate plant or tissue expander during RT
No diff in chest wall toxicity at 3.5Yr
Similar levels of physical well-being 6 months after treatment (p=0.71)
Treatment breaks were significantly fewer (3% vs. 8% w/ Hfx, p=0.03)
No diff in chest wall treatment effects
No diffs in LR or AEs
Early acceptable outcomes in MHFx w/ reconstruction
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EBCTCG meta-analysis 2023
Updated meta-analysis of 16 RCTs (14,324 patients) of regional lymph node RT vs. no regional lymph node RT in women w/ early IDC
1º EP: Recurrence at any site, breast cancer mortality, non-breast-cancer mortality, and OS
improved LRR and BCSM in RNI
greater N burden, greater abs benefit
1-3 N+ still have benefit
RT after NAC
We know breast cancers that respond to CHT are different biologically
NSABP B18/27: LRR after Neoadjuvant Therapy
combined analysis of 2 studies
NAC: AC or ACT in palpable breast cancer
recurrence higher in pts w/o PCR in breast/nodes vs PR
also greater LR in N+ after NAC
also influenced by tumor subtypes
no overlap in EFS for PCR vs PR in TNBC
however, ER+ dz does have overlap (less of a EFS benefit)
RNI Recommendations cN+ → ypN+
Persistent nodal disease
after NAC, even micrometastases, both indicative of
systemic therapy resistance
and
predictive of additional non-sentinel lymph nodes
RNI is appropriate
What about PCR in Nodes sp NAC?
NSABP-B-51
Mamounas, SABCS Presentation, 2023
RCT phase III trial
1º EP: IDC-RFI (recurrence free interval)
m f/u: 60 mo
no diff in RFI
no diff isolated LRR Free interval w/ RNI
SGA: surgery had measurable diff, but nothing sig
exploratory analysis showed potential diff in biology
TNBC and ER+
More of a benefit to TNBC
RNI Recommendations cN+ ➔ ypN0
Among pts who are initially N+ (cN1) and become
pathologically N0
after neoadjuvant systemic therapy,
5 yr f/u data
suggests
limited benefit to RNI in this setting
However, consideration of individual pt characteristics including surgical management and receptor status/tumor biology remains very important in determining the role of nodal irradiation
Genomic Signatures to guide RT
LRR in N+ pts by RS
Retrospective evaluation of 1065 ER+ N+ pts treated w/ adjuvant CHT plus TAM on NSABP B-28, using 21-gene recurrence score (RS) assessment
m f/u: 11 yr
10-yr cumulative incident of LR
RS low: 3%
RS intermediate: 7%
RS high: 12%
LRR events list:
RS high: No. 315, 39 events
RS intermediate: No. 364, 25 events
RS low: No. 386, 16 events
P < .001
Conclusions:
RS was an independent predictor of LR a
long w/ pathologic nodal status and tumor size
Mamounas, et. al., JNCI J Natl Cancer Inst, 2017
LRR by Oncotype
Retrospective evaluation of SWOG S8814, a phase 3 RCT of postmenopausal women w/ HR+ N+ IDC treated w/ either TAM, CAF (cyclophosphamide, doxorubicin, and fluorouracil) CHT followed by TAM, or concurrent TAM and CAF
Association between the
21-gene expression
assay recurrence score and LR
m f/u for 316 pts: 8.7 yr
121 pts w/ low recurrence score
195 pts w/ intermediate or high recurrence score
Among 252 pts w/ mastectomy and w/o RT, LR at 10 yr:
8% low recurrence score vs. 17% intermediate/high recurrence score (p = .03)
Scores do stratify LR10 risk
Subset of pts w/ 1-3 N+ who underwent a mastectomy w/o RT (n = 165)
↑LR was observed in intermediate or high recurrence score group:
2% low recurrence score
11% intermediate/high recurrence score
p = .051
No diff by recurrence score was found in the 10-yr rates of LR among those w/ 4 or more N+ who received a mastectomy w/o RT
26% low recurrence score
27% intermediate/high recurrence score
p = .27
Woodward, et. al., JAMA Oncology, 2019
MA39/TAILOR RT
Inclusion Criteria
pT1-T2N1 or pT3N0
ER+, HER2-
Oncotype DX RS ≤ 25
Stratification
BCS or Mastectomy
ALND or SLNB
Adjuvant CHT
OncotypeDX RS (0-10 vs. 10-25)
SLNB: 1-2+ / ALND: 1-3+
RCT
Regional RT
WBI+RNI or CW+RNI
No Regional RT
WBI or No RT
10-yr RFI
1º EP: RFI at 10 yr
Actively accruing, estimated enrollment 2140 pts
Parulekar, et. al., JCO, 2019
RADCOMP
Sparing cardiac toxicity with particle therapy
PARABLE
UK trial
mHFx
DBCG Proton
mHFx
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