2. Surgical HOT Topics Tari King, MD
Chief, Breast Surgery, Dana-Farber/Brigham and Women’s Cancer Center
Associate Chair for Multidisciplinary Oncology
Department of Surgery, Brigham and Women’s Hospital
Anne E. Dyson Associate Professor of Surgery,
Harvard Medical School

3. Surgical HOT Topics Selecting the optimal local therapy in DCIS
Some or none?
Interplay between age and molecular subtype and selecting local therapy
When can we de-escalate local therapy ?
Neoadjuvant therapy
Management of the axilla (covered in separate talk)

4. DCIS: Increased Incidence
DCIS Overall
Comedo DCIS
Non-comedo DCIS
LCIS
SEER
Li et al, Cancer Epidemiol
Biomarkers Prev 2005
Older Age
Present SEER study
For the last few years we have heard more about DCIS … not so surprisingly When one considers the increased incidence of this diagnosis over the last three decades, shown here in two different datasets from SEER, it now estimated as affecting over 500,000 women, it is easy to understand the heightened interest in this topic
SEER
Bleyer A et al NEJM 2012

5. DCIS: Local Therapy Trends and Survival
ASCO 2014: Wormi et al, Trends in treatment patterns and outcomes for DCIS patients: A SEER population-based analysis.
Clinical trends in type of
local therapy for DCIS:
Oldest median age:
No treatment or Lx w/o XRT
Youngest median age:
Bilateral Mastectomy
High grade DCIS:
Lx w/ XRT or Unilat. Mast
Size > 40 mm:
Unilateral Mastectomy
Over this time period we have also seen some interesting trends in local therapy for DCIS in a 2014 presentation at ASCO - Dr Wormi and colleagues used the SEER database to report on trends in treatment patterns and outcomes for patients with DCIS. Study included just over 120,000 women with DCIS treated between 1991 and 2010 and demonstrated an overall decreased use of mastectomy or lumpectomy alone and increased use of lumpectomy and RT over this time period but they also demonstrated that clinical and pathologic variables are associated with different local therapy methods.
121,080 DCIS
SEER

6. DCIS: Cancer Specific Survival
And not surprisingly here were the outcomes– the survival curves are super imposable for mastectomy, Lumpectomy with XRT and lumpectomy alone in this very large population of DCIS that included the spectrum of risk for DCIS
ASCO 2014: Wormi et al. A SEER population-based analysis.

7. Goal of DCIS Local Therapy: Prevent First Invasive Breast Cancer
Years since IBTR
Invasive
DCIS
Breast Cancer Mortality
So or goal in treating DCIS is not to improve survival but to prevent invasive recurrence- The importance of this is illustrated by these two datasets - the combined analysis of NSABP B17and B24 and the long term followup from EORTC both demonstrating substantially higher rates of breast cancer mortality for patients who experience an invasive recurrence after first treatment of DCIS.
NSABP B17/B24
Combined Analysis
EORTC 10853
Wapnir et al. JNCI 2011, Donker et al. JCO 2013

8. Personalizing local therapy…. DCIS
Treatment or Observation?
Mastectomy or Conservation?
To Radiate or not to Radiate ?
How do we select patients ?
Faced with these options how do we choose

9. ECOG 5194: Observation after Lumpectomy for Low risk DCIS
SABC P : Solin LJ, et al. Local excision without radiation for ductal carcinoma in situ: 12-year results from the ECOG E5194 study
Cohort 1: low or intermediate grade DCIS, size ≤ 2.5cm
Cohort 2: high grade DCIS, size ≤ 1.0cm
To review some of these other findings - At SABC in 2014 we saw the 12 yr followup from ECOG 5194 – this was a trail where low risk DCIS patients were selected based on standard histopathologic criteria – just to remind you this study enrolled patients into two cohorts – cohort 1 – low or intermediate DCIS less than 2.5cm and cohort 2 high grade DCIS less than 1 cm. you can see that in both groups the median lesion size was less than one cm and over 80% of pts had margins of at least 5mm and 25-30% of pts took tamoxifen
Solin et al. SABC 2014

10. No difference in 12 yr OS: 84% vs 83%
12 Year Outcomes ECOG 5194
In-breast Recurrence
Cohort 1
“Lower risk”
Cohort 2
“Higher risk” p
ALL
14.4%
24.6%
0.003
DCIS
7.3%
12.6%
0.02
Invasive
7.5%
13.4%
0.08
at 12 yrs of followup rates of in breast recurrence in lower risk low risk group (selected by clinical criteria ) was 14% and in the higher risk low risk group the rate of recurrence was 25% - in both cohorts there was an equal distribution between DCIS and invasive recurrences and there really is no evidence of a plateau
No difference in 12 yr OS: 84% vs 83%
Solin et al. SABC 2014

11. 12 Gene DCIS Recurrence Score™ ECOG E5194
All Local Recurrence
Invasive Local Recurrence
Many of you will remember that it was this E5194 dataset that was first used to demonstrate the prognositic ability of the GH DCIS Score – this was presented at SABC several years eariler by Larry Solin and published in the JNCI in in this low risk cohort the DCIS score was able to stratify pts into low intermediate and high risk groups for any local recurrence – here you see very similar breakdown – low risk pts have a 10% risk of an ipsilateral event at 10yrs and high risk pts have a 25-30% risk at 10yrs. But in this dataset they went a step further – looked at predicting risk of invasive recurrence on the left where there appeared the low risk group truly appeared to have a very low risk of invasive recurrence.
N=327, “low risk” DCIS
<2.5cm, low-int grade or <1cm, high grade
margins > 3mm
Solin et al. JNCI 105: 2013

12. Local recurrence = DCIS or invasive,
Validation of the 12 Gene
DCIS Recurrence Score
SABC S5-04: Rakovitch et al. A population-Based Validation Study of the DCIS Score Predicting Recurrence Risk in Individuals Treated by BCS
Path reports pure DCIS ; linked with Ontario Cancer Registry
Central path review
At SABC in 2014, Rakovitch and colleageus presented the results of their validation study which was a population based cohort of pts with pure DCIS treated between 1994 and 2003 in Ontario. They identified 1658 pts,, tissue blocks were retrieved for 828 pts – all were subject to central path review and after exclusions for presence of invasive disease, positive margins or insufficient material for analysis the study cohort comprised 571 pts with DCIS treated with BCS alone – the statistical plan was pre-specified with 3 risk groups as defined in the earlier study and local recurrence was defined as DCIS or invasive disease > 6 months after tx DCIS.
Primary objective – to determine if score associated with risk of LR in this cohort
DCIS treated with BCS alone, neg margins
To determine if score independently assoc with LR after adjusting for other significant clincial and path variables
Local recurrence = DCIS or invasive,
≥ 6 mos after dx DCIS
SABC 2014

13. SABC S5-04: Rakovitch et al
SABC S5-04: Rakovitch et al. A population-Based Validation Study of the DCIS Score Predicting Recurrence Risk in Individuals Treated by BCS
Kaplan-Meier 10yr Risk of LR
by DCIS Score Risk Group
Any Local Recurrence
In this large series of unselected cass – the DCIS score was prognostic for risk of any local recurrence shown on the left with the low risk group having a 13% risk of recurrence at 10yrs and the intermediate and high risk groups having about a 30% risk of LR – on the right again with see the score was also associated with risk of invasive recurrence on the top and non-invasive recurrence on the bottom. The authors concluded that the DCIS score provided useful information that could be used when discussing treatment options with patients.
SABC 2014

14. 12 Gene DCIS Recurrence Score™
Kaplan-Meier 10yr Risk of LR by DCIS Score Risk Group
Ontario Cohort
26.7%
25.9%
When you put the data from these two studies together it is remarkably consistent – the low risk group hovers around 10-12% and the other two groups around 25-30%
10.6%
N=327, low risk DCIS
<2.5cm, nuc gd or <1cm gd 3
margins > 3mm
N=571
58% int gd, 32% high gd
26% <1cm, 25% > 1cm, 49% NA
margins neg

15. Many Paths One Destination
DCIS Local Therapy:
Many Paths One Destination
Excellent survival for lumpectomy +/- XRT and Mastectomy in all age groups
“Good” Risk DCIS has lower risk of in-breast recurrence
DCIS Risk Score can be used to give individualized risk information
Balanced discussion of risks and benefits of radiotherapy – not a one size fits all approach
Need patient reported outcomes regarding trade-offs of treatment side effects versus worry about recurrence
So when it comes to personalizing therapy for DCIS -

17. Ipsilateral invasive disease at 5 years

18. The COMET Trial

19. COMET Trial for Low Risk DCIS
Registered and randomized (n=1,200)
GROUP 1: GCC (n=450)
Surgery +/- Radiation choice for endocrine therapy
MMG q 12 months x 5 years; usual care for recurrent disease
GROUP 2: AS (n=450)
choice for endocrine therapy
MMG q 6 months x 5 years, usual care for invasive progression
Registry Group:
Randomized but declined allocated arm (n=300)
GCC or AS
Follow up per usual care
Patients randomized to AS strongly encouraged to consider endocrine therapy of choice
Eligiblity criteria:
Age ≥ 40
Grade I/II DCIS without invasive cancer
ER(+) and/or PR(+), HER2(-) if tested
No mass on PE or imaging
Endpoints:
2, 5, and 7-year invasive cancer dx
2, 5, and 7-year OS, DSS
PRO endpoints (QOL, fear of cancer recurrence, body image)

20. Invasive Cancer Age and Molecular Subtype
Both impact risk of local-regional recurrence and survival
Increased risk imparted by young age differs among breast cancer subtypes
Favorable interaction between older age and molecular subtype
The relationship between age and molecular subtype is complex. Both impact risk of LR recurrence and survival, yet it is now clear that the increased risk imparted by young age differs among breast cancer subtypes such that young age is no longer a predictor of outcome in Her2 positive or TN disease. And we have seen a favorable interaction between older age and molecular subtype – driven by the predominance of luminal tumors in the older age groups.

21. Biology and Pathology Features More Common in Young Women
Larger T size, palpable tumors
High Grade
Poorly differentiated
Lymphovascular invasion
Increased proliferation (S-phase, Ki67)
Hormone receptor negative
Her 2 negative
BRCA associated
Increased risk LR
Inferior Survival
Focusing on biology – It is well known that women under the age of 40 frequently present with larger, palpable tumors that are high grade, poorly differentiated tend to be HR and Her2 negative and many young women will be found to harbor a BRCA mutation highlighting the need for appropriate referral for genetic testing in young women and these factors have classically been associated with an increased risk of LR and overall poorer outcomes.
Azim HA et al. Breast Cancer Res 2014

22. Age and Intrinsic Subtypes
As we incorporate molecular classification into our assessments – here looking at the relationship between age and PAM50 subtypes in a pooled analysis of 9 publically available microarray datasets – we recognize that our younger patients are more likely to have tumors of the basal-like phenotype (represented by the red portion of the bar and less likely to have luminal tumors (in the two shades of blue) and the exact opposite is true for our older patients – in this dataset the incidence of luminal tumors increased from 30% in the younger cohorts to 71% in the oldest cohort and the incidence of basal like tumors peaked at 44% in the younger patients decreasing to 9% in the older patients.
9 pubilically available microarray datasets pooled for a total of 3947samples ( ) = age and PAM50
Complete IHC available for 49% samples (1940pts))
Distribution of intrinsic subtypes by age
Incidence of luminal tumors combined (A and B) increases with age (p<0.0001) and the incidence of basal-like tumors decreases with age (p<0.0001)
Oldest age cohorts (70-93) basal like and Her2 enriched, 9% and 11% respectively
20% elders with basal-like or Her2 enriched indicates that many have aggressive subtype
As expected luminal A subtypes had better outcomes than more aggressive
Incidence of luminal tumors increases with age: 30% to 71%, p<0.0001
Incidence of basal tumors decreases with age: 44% to 9%, p<0.0001
Jenkins et al. Oncologist 2014

23. Age and IHC Surrogates for Subtype
Among HR+/Her2- patients
Younger patients less likely
to have Luminal A/B tumors
67% vs 86% (p=0.006)
Drill down even further looking at age and the IHC surrogates for subtype – we see that among all pts classified as HR+/HER2 – by IHC, younger patients are still less likely to actually have a luminal tumors by gene expression – only 67% of younger pts with HR+/Her2- disease actually have luminal tumors vs 86% in the older patients and if one examines pts who are TN by IHC, younger patients have a higher predominance of true basal cancers 80% vs older pateints with TN disease where only 57% classify as true basal cancers by PAM50.
Of all HR+/Her2- , 50% luminal A and 29% luminal B with % varying across age groups )p=0.006)
67% in the youngest age group luminal A/B compared to 86% in the oldest age group
% of TNBC who are basal like decreased with age – 80% for those < 60yrs, 70% for those 60-69, 57% for those > 70
OF her2-/hr+ 61% were Her2 enriched and 24% were basal like , no differences by age group
HR+/Her2 + overall 32% were luminal B, varied from ~20% in those 60 to approximately 50% in those 60 and older
Among TNBC patients
Younger patients more likely
to have basal-like tumors
80% vs 57% (p=0.003)
Jenkins et al. Oncologist 2014

24. Is age an independent prognostic factor or is age simply a reflection of biology?
These observations lead to the question of whether age is truly an independent prognostic factor or is age simply a reflection of biology

25. Age and IHC Subtype – HER2
Population based analysis, British Columbia, 3046 patients < 50 yo
Relapse Free Survival
Overall Survival
N=1101
This population based analysis from BC ~3000 women < 50 years of age addresses this question quite nicely. Using IHC surrogates for subtype they examined outcomes over two time periods and , comparing women under the age of 40 with those aged 40-49
Here we see in the HER2 enriched subtype, age < 40 years depicted in the light gray line was associated with inferior 5-year RFS on the left and OS on the right in the earlier time period (5-year RFS: 39% versus 58%, p = 0.039; OS: 49% versus 66%, p = 0.017), but not in the later years following the introduction of taxanes and trastuzumab into clinical practice where there was no difference in outcomes by age. (5-year RFS: 81% versus 84%, p = 0.879; 5-year OS: 89% versus 89%, p = 0.879).
N=1945
Sheridan W et al BCRT 2014

26. Age and IHC Subtype – TNBC
Relapse Free Survival
Overall Survival
N=1101
N=1945
<40 5yr RFS 60%
<40 5yr RFS 78%
<40 5yr OS 67%
<40 5yr OS 82%
These are the same graphs for the TN subtype. There was no effect of age observed for either RFS on the left or OS on the right for the triple-negative subtype in either time period. but importantly the outcomes for both age groups improved over time. Among women < 40 years of age, 5-year RFS improved from 60% to 78% (p = 0.014) and 5-year OS improved from 67% to 82% (p = 0.011).
The observation that young age is a prognostic factor for hormone receptor positive and HER2 positive subtypes, but not TNBC, was also demonstrated in two Korean studies of patients < 35 years of age treated prior to the routine availability of trastuzumab6, 7. However, in the large Herceptin Adjuvant (HERA) trial, age < 40 years was not associated with inferior disease-free survival (DFS) or OS among patients treated with chemotherapy plus trastuzumab.8
Collectively, these findings demonstrate that advances in systemic therapy have contributed to improvements in survival across all subtypes and have eliminated the impact of age in HER2 positive breast cancer, yet a significant disparity still exists for women < 40 years of age with hormone receptor positive breast cancers; likely driven by the luminal B subtype.
Sheridan W et al BCRT 2014

27. Age and IHC Subtype – HR+/HER2-
Relapse Free Survival
Overall Survival
N=1945
N=1101
Finally, Within the hormone receptor positive subgroups, both recurrence-free survival (RFS) and overall survival (OS) also improved over time with increasing use of anti-estrogen therapy; however, both outcomes remained inferior for women < 40 years of age (light gray line) as compared to those years of age shown in the black line, the authors suspect this was due to the influence of luminal B cancers as they were not able to separate the two luminal subtypes in their analysis ( : 5-year RFS 79% versus 92%, p < 0.001; and 5-year OS 89% versus 95%, p < 0.001).
Sheridan W et al BCRT 2014

28. Subtype, Young Age and BCS mortality
17,575 women, Stage I-III breast cancer 8 NCCN centers 1/ / pts ≤40yrs, BCS mortality by subtype, ref 51-60yrs
Age ≤ 40yrs N
HR death (95%CI)*
HR death (95%CI)^
Luminal A
510
2.1 ( )
1.7 ( )
Luminal B
698
1.4 ( )
1.2 ( )
HER2
189
1.2 ( )
1.1 ( )
TNBC
478
1.4 ( )
1.3 ( )
However We now have data addressing this issue from a slightly larger dataset comprised of 17,500 women treated for stage I-III breast cancer at 8 NCCN cancer centers between Partridge and colleagues examined the relationship between BCS mortality and subtype among those < 40yrs old with the referent group representing those aged 51-60…On MVA adjusting for typical confounders listed at the bottom of the slide they reported increased hazard for BCS mortality in both luminal A and lum B patients – HR 2.1 and 1.4 respectively and no influence of age for the her2 and TNBC subytpe However, after further adjustments for method of detection – only the luminal A subtype remained associated with an increased hazard for death. There is much speculation as to why this may be true – one potential explanation may be adherence to hormonal therapies which we know can be challenging for some of our younger patients.
with 20,025 stage I-III pts – excluded those with previous cancer dx, missing IHC and no followup = pts
1916 <=40 at diagnosis, mean age 35yrs, mean age of women > 40yrs was 57yrs
Median followup 6.42 years
Younger women more likely to be non-white, premenopausal, more educated, and employed or in school
Higher stage and grade, luminal B, TNBC or HEr2
Large national sample, control of tumor subtype – young age prognositic in certain subtypes but not others
HER2 or TNBC no clear increased risk of breast cancer mortatlity among those <=40 years compared to women 51-60yrs
In the more aggressive subtypes outcomes are similar
Luminal breast cancer age does remain an independent prognostic factor
May refect inadequate therapy, lower treatment efficacy, less therapeutic adherence and persistence as well as residual differences in tumor biology
*MVA adjusting for race/ethnicity, insurance, employment, center, education,
treatment, stage, grade, year of diagnosis
^Also adjusted for method of detection (symptomatic or screened)
Partridge A et al. JCO 2016

29. What does this mean for local therapy?
So what does this mean for local therapy?

30. Time-trends in LR following BCT MDACC experience over 27 years
1355 pts, Stage I-II breast cancer
median follow-up of 7.4 years
5-year IBTR rate 4.5%
7.1%
6.4%
4.2%
1.3%
Age ≤ 50
Age > 50
9.1%
2.6%
1.4%
1.2%
With increasing use of systemic therapy over the last 3 decades we have seen rates of LR decreasing for all patients. In this report from the MDACC, 5yr rates of local recurrence decreased from 7% in the early 1980s to less than 2% in the mid 1990s and while this decline was seen both in patients < 50 and > 50 the biggest absolute differences were in the younger patients. On MVA for pts under 50 yrs of age the use of chemotherapy was the only significant factor for improved IBTR free survival.
Cumulative 5-year IBTR rates declined throughout the 27-year period
Primarily due to a decline in the incidence of IBTR in pts <50 at diagnosis, reasons are likely multifactorial reflecting changes in diagnostic imaging, surgical and pathologic techniques, and most importantly the use of systemic therapy
MVA: pts ≤ 50 y.o. chemotherapy only significant factor for improved
IBTR free-survival, HR 0.38, (95% CI ) p=0.001

31. Age, Molecular Subtype, LR after BCT
Multi-institutional cohort 2233 pts, all treated BCT,
Excluded pts that received neoadj therapy and/or anti-Her2 therapy
Median follow-up 106 months
Overall 5yr LR 3.1%
8yr LR
Lum A
1.8%
Lum B
5.5%
Lum Her2
2.2%
Her2*
11.7%
TNBC
9.8 %
Incorporating subtype into the equation…In this very recent publication including 2233 pts treated with BCT between 1998 and 2007– the overall 5yr LR rate was 3.1% - when examined by subtype we see very low rates of Local failure at 8yrs for the luminal tumors and higher rates of local failure for the TNBC and Her2 + subtypes although this dataset did not include the use of anti-Her2 therapy.
On MVA factors associated with LR included – the luminal B, Her2 and TNBC subtype, age < 50 and an increasing number of LN - I would argue that these same factors would be associated with LR after mastectomy …
MVA factors associated with LR: luminal B (HR 2.46), HER2 subtype (HR 5.42),
TNBC (HR 4.33), Age <= 50yrs (HR 0.56)
Increasing number of nodes (HR 1.06 per involved node)
Braunstein et al. BCRT 2017

32. Age, Molecular Subtype, LR after BCT
Multi-institutional cohort 2233 pts, all treated BCT,
Excluded pts that received neoadj therapy and/or anti-Her2 therapy
Median follow-up 106 months
actuarial 10yr LR 4%
KM Estimates of 10 yr Local Recurrence Risk
Age
pts
Luminal A
Luminal B
Luminal-HER2
HER2
TNBC
Overall
2.5% 6%
12%
11%
23-46yrs
504
6.3%
9.3%
3.5%
29.3%*
47-54yrs
557
0.6%
3.2%
17.3%
10.8%
55-63yrs
603
1.7%
3.0%
2.2%
5.3%
7.0%
64-88yrs
569
1.8%
6.2%
3.3%
20.5%**
If we drill down deeper into this dataset – now looking at KM estimates for 10yr LR risk by age and subtype – we see very respectable rates of 10 LR among the youngest group for all except the Her2 subtype ( again without the benefit of antiher2 therapy) and at the other end of the spectrum similarly low and in some cases very similar rates of LR by subtype among the older patients.
I’d like to draw your attention to the TNBC subtype – which we clearly associate with higher rates of Local failure – these data demonstrate that there is really no difference in the risk of LR by age for patients with TNBC…
*No anti-her2 therapy **small numbers
Braunstein et al. personal communication

33. Radosa et al. Ann Surg Oncol 2017
TNBC Outcomes and Age
1930 Stage I-III TNBC treated at MSKCC
Cumulative 5yr rates (95%CI)
Age ≤ 40 yrs
N=289
Age > 40 yrs
N=1641 p
Overall Local Recurrence
3.9 ( )
4.5 ( )
0.82
BCT (n=1066)
6.4 ( )
4.5 ( )
Mastectomy (n=864)
2.3 (0-4.5)
4.5 ( )
Regional Recurrence
1.9 ( )
1.8 ( )
0.57
Distant Recurrence*
17.9 ( )
11.0 ( )
<0.01
Disease Free Survival
75.3 ( )
77.7 ( )
0.94
We also demonstrated this is a dataset of 1930 TNBC pts treated at MSKCC between 1998 and 2011 – when we compared outcomes between those < = 40 to those over 40 at diagnosis there was no difference in overall rates of LR 3.9% vs 4.5%, no difference in LR by type of operation performed and no difference in regional recurrence. Younger patients did have higher rates of distant recurrence in this dataset but when competing risks are factored in there was overall no difference in disease free survival on the basis of age < or > 40. On MVA tumor size, LVI, nodal positivity were associated with increased risk of DR.. Age and type of surgery were not predictors of either LR or DR..
MVA: Tumor size, LVI and nodal positivity assoc with increased risk of DR
Age and type of surgery not predictors of LR or DR
Radosa et al. Ann Surg Oncol 2017

34. Subtype, Surgery and RFS
2474 women, Large Korean database (SNUHBCC),
199 (8%) < 35 yo; median follow-up 59.9 months
Recurrence Free Survival
Subtype N
Mastectomy vs BCT
HR (95%CI)
HR+/HER2-
1186
0.82 ( )
HR+/HER2+
213
1.08 ( ) TN
513
1.54 ( )
HR-/HER2+
261
0.87 ( )
Focusing specifically on the choice of surgical procedure - mastectomy vs BCT looking at all subtypes – this Korean dataset of almost 2500 women treated between 2000 and 2005 also fails to support the use of bigger surgery in any subtype – RFS is no different based on the type of surgery performed – escalating surgical therapy is not warranted even in the more aggressive subtypes…
Bigger surgery not better in any subtype
Kim et al. World J Surg 2011

35. Breast Cancer Young Women BCT vs Mastectomy
British Columbia Cancer Agency,
965 pts aged 20-39yrs T1/T2, N0/1
Median followup 14.4yrs
15yr rates
BCT
N=616
MRM
N=349 p
LRFS
85.4%
86.5%
0.95
LRRFS
82.2%
81.6%
0.61
DRFS
74.4%
71.6%
0.40 OS
74.2%
73.0%
0.75
This is also true if we Focus specifically on young women – these data from the BC Cancer Agency demonstrate that among 965 pts aged 20-39, treated with BCT or MRM, there was no difference in LRFS, LRRFS, DRFS or OS at a median followup of 14 yrs. Escalating surgical therapy is also not warranted in young women..
BCT not associated with reduced survival
MV analysis: age 20-29, node status, LVI, positive margins, grade 3, central/medial
Tumor location associated with worse BCSS and OS
Cao et al. Int J Rad Oncol 2014;90

36. 2013 SSO/ASTRO Guidelines on Margins for BCS with whole breast RT Stages I and II Invasive Breast Cancer
Multidisciplinary consensus panel
Meta-analysis of margin width and IBTR from a systematic review
(33 studies, including 28,162 patients)
Positive margins are associated with a 2-fold increase in IBTR
Negative margins (no ink on tumor) minimize the risk of IBTR
No evidence that wider margins are warranted in younger pts
No evidence that wider margins are warranted in more aggressive subtypes
When BCT is pursued of course we realize the importance of negative margins… in 2013 she also led the multidisciplinary consensus panel to establish a margin guideline for invasive breast cancer. The panel reviewed the evidence from 33 studies, including over 28,000 pts as presented in the metaanalysis by Housammi et al. and concluded that a negative margin, defined as no tumor on ink, minimized the risk of local recurrence and there was no evidence that bigger margins were better. Importantly this guideline applies to all age groups and all subtypes - of patients….the panel found no evidence that wider margins were warranted in younger patients…no evidence that wider margins are warranted in more aggressive subtypes
ASCO approved the margins guideline for patients with early stage invasive disease. This was the result of a multi-disciplinary consensus conf panel which reviewed data from a meta-analysis
They concluded that …
Moran et al. JCO 2014

37. Brinker Award Lecture Monica Morrow- Making Less More
At SABC this year in her Brinker Award lecture, Dr. Morrow showed some prelim data that the margin consensus is actually having an impact. These are unpublisehd data from the CanSORT study – a survey study of women with newly diagnosed breast cancer and their physicians – population based sample from Georgia and LA counties – you can see that between 4/2013 and 4/2015 – so the first two years of the consensus that rates of BCS are increasing (blue portion) and rates of unilateral and even bilateral mastectomy appear to be decreasing.

38. Brinker Award Lecture Monica Morrow- Making Less More
If you look more closely at the data looking at rates of additional surgery by margin status – in the green bar we see a decrease in the number of pts going back to the OR for additional surgery with margins that are negative defined as > 1mm (green bar) and negative but close in the red bar defined as (<1mm).
So we are doing less surgery to obtain some arbitrary wider margin width than no tumor on ink and as a result fewer pts are choosing mastectomy for invasive cancer

39. 2016 SSO/ASTRO Guidelines on Margins for BCS with whole breast RT in DCIS…
Multidisciplinary consensus panel
Meta-analysis of margin width and IBTR from a systematic review
(20 studies, including 8,651patients)
Positive margins are associated with a 2-fold increase in IBTR
A 2mm margin minimizes the risk of IBTR compared with smaller negative margins
More widely clear margins do not significantly lower this risk
Negative margins less than 2mm alone are not an indication for mastectomy
Factors known to impact rates of IBTR should be considered when determining the need for re-excision
We also now have The DCIS margin consensus which was recently published – after following a siimilar systematic process – the panel concluded that for pure DCIS – again positive margins assoc with a …
A 2 mm margin..
We anticipate that we will see data demonstrating the impact of this guideline in the coming years although this may not have quite as profound an impact as the invasive cancer guideline.
Morrow et al JCO

40. Can we de-escalate therapy ?

41. Can we de-escalate treatment?
CALGB 9343
Can we de-escalate treatment for these pts – this is the 5yr data from the CALGB 9343 trial of lumpectomy +tamoxifen with or without radiation therapy in women > 70 with early breast cancer…. Although these results were quite promising – small absolute dfferences in LR at 5 yrs but no difference in mastectomy free survival, distant DFS or OS…when published in these data did not have a big impact in clinical practice..
At 5 yrs Hughes and colleagues demonstrated that although LRR rates were higher in the tam only gp (4% vs 1%) there was no difference in rates of mastectomy, distant DFS or OS..
Tam Alone (319)
Tam +RT (317)
LRR at 5yrs 4% 1%
<0.001
5yrs Mastectomy free survival
98%
99% NS
5yr distant DFS
5yr OS
86%
87%
Hughes K et al. NEJM 2004

42. 12 yr update CALGB 9343 Mastectomy-free survival Overall Distant DFS
10yr LRR free survival
98% vs 90%
we now have 12 year data from this trial demonstrating 10 yr LRR free survival of 98 vs 90% and still no difference in mastectomy rates, distant DFS or OS….
How much more data do we need to convince ourselves that omitting RT in women over the age of 70 with early stage ER+ disease is safe and appropriate therapy
Hughes JCO 2013

43. Not all patients benefit from axillary staging….
Management of the axilla ?
CALGB 9343 trial of clinical stage 1 (T1N0M0) ER+
636 women ≥ 70yrs of age
pathologic node status confirmed in only 244(38%)
392 (62%) patients no axillary staging or treatment
All 392
Tam Alone
Tam + RT
10yr rate
Axillary failure
1.5 %
6/200
(3%)
0/192
(0%)
What about the axilla – Dr Morrow reviewed yesterday the progress we have made in doing less ALND in both cN0 and CN1 patients with a good response to systemic therapy… there is also data in properly selected patients we can safely omit axillary staging altogether. In the CALGB trial that we just looked at– 392 pts (62%) had no axillary staging or treatment – again all pts had 5 yrs of tamoxifen and half also received RT… when looking at 10yr rates of axillary failure in the entire group of 392 pts the rate was 1.5%, it was 3% in the group with out RT and 0 in the group with RT
In this trial
Not all patients benefit from axillary staging and
These findings are consistent with growing body of evidence ….
Not all patients benefit from axillary staging….

44. Trials +/- ALND Early Stage Favorable Breast Cancer
Clinical features
f/u TX
Axillary relapse
No ALND ALND
Martelli et al
2014
238
65-80
T1N0
88% ER+
15yrs
Tam + RT
5.2%
109*
90%ER+
IBCSG 10-93
473
≥60
T1-3cN0
80%ER+
6.6yrs
Tam
22% RT 3% 1%
CALGB 9343
636
≥70
cT1N0
ER+
10yrs
Tam +/-RT
1.5%
There have also been several RCT looking at axillary relapse with or without ALND in older pts with early stage favorable tumors - all patients received tamoxifen with or with out RT – all trials show very low rates of axillary relapse and no difference in DFS, breast cancer mortality or OS based on the performance of an ALND…again suggesting that we may be able to de-escalate therapy in women with early stage favorable disease where the decision for adjuvant hormonal therapy has already been made.
Martelli et al. compared ALND versus no-ALND in women aged years with primary cT1N0 (<2 cm) breast cancer treated with BCS followed by RT and tamoxifen and reported a 6% (95%CI 0%-12.6%) crude cumulative incidence of axillary recurrence in the no-ALND arm compared to zero in the ALND arm with no difference in 15-year BCSS, DMFS or OS between groups. These findings are supported by the results of the IBCSG trial where no BCSS benefit was observed after ALND in patients ≥60 years of age surgically treated for ER+, cN0 breast cancer followed by tamoxifen. Furthermore, transiently improved quality of life (mainly during the first year after treatment) was observed in patients who did not receive ALND.
Martelli G, et al. Axillary Dissection versus No Axillary Dissection in Older Patients With T1N0 Breast Cancer. Ann Surg 2012;256:
International Breast Cancer Study Group. Randomized Trial Comparing Axillary Clearance Versus No Axillary Clearance in Older Patients With Breast Cancer: First Results oof IBCSG trial JCO 2006;24:
No differences in disease free survival, breast cancer mortality or overall survival by ALND
* Out of trial patients; 71 with AD, 38 no AD

45. De-escalating Local Therapy
Opportunities for further de-escalation in patients with favorable disease characteristics; selected by traditional clinico-pathologic features or by molecular profiling
Ongoing trials…..
US: PRECISION – No RT for low risk PAM 50
Canada: LUMINA – No RT for low risk, IHC and Ki67
UK: PRIMETIME – No RT for very low IHC 4+ c score
EIO: SOUND - SLN vs axillary observation, normal US
Others…