Eva María Ciruelos Gil. Madrid

1. Actualización 2019:
San Gallen, ESMO, SABCS
Dr Eva M Ciruelos
Servicio Oncología Médica, Unidad Cáncer de Mama
Hospital Universitario 12 Octubre
HM CIOCC

2. Aspectos significativos de St Gallen 2019

3. Treatment guidelines are no longer driven exclusively by the
anatomic stage of the tumor or the histological subset of breast cancer. Decisions about
optimal surgical, radiation therapy and medical approaches are increasingly tailored
based on the initial response to neoadjuvant systemic treatment (NST). These
developments demand that routine care be provided by an experienced
multidisciplinary team.

4. Sophisticated pathology and genomic signatures assays substantially refine the
anticipated prognosis for long-term outcomes and thus inform treatment
recommendations.
- For some patients there is a clear move to escalate therapy, such as longer durations of antiestrogen
treatment, more utilization of ovarian function suppression (OFS), treatment
for residual tumor after neoadjuvant systemic therapy, and dual targeting with anti-
HER2 drugs.
- In other settings, there is a movement to de-escalate treatment, including
the shortening or omission of adjuvant chemotherapy, the avoidance of axillary surgery,
and shortened courses of radiation treatment.

5. Tratamiento quirúrgico: márgenes y V Axilar
Nipple and skin sparing mastectomy.
Caution ir close proximity of the tumor to the skin
Controversy fon preservation of nipple areolar complex if central tumors

6. Tratamiento quirúrgico: márgenes y V Axilar
- In case of focally positive margins: re-excision (if extent not minimal)
- If area of focally involved margin < 1mm, outweight risk and burden of re-
excision
- Recents studies in population based registries: limited focal positive
margins with RT with a boost to the primary tumor bed associated with low risk
of tumor recurrence (2,9 vs 1,1 % at 5 years)

7. Tratamiento quirúrgico: G Centinela y V Axilar
- Sentinel node biopsy (SNB) as standard approach in cN0 and breast
conserving sx
- Elderly pts with clinical stage I and favorable biology: may not need SNB
(IBCSG 10-93)
- ACOSOG Z11 trial, a study of women with cT1-2, cN0 cancers
tumor involvement of 1 or 2 sentinel lymph nodes
completion axillary dissection is not indicated when patients
will be receiving post-lumpectomy radiation therapy and
appropriate systemic adjuvant therapy
- If tumor size > 5cm and 1-2 positive nodes. Consider omitting axillary
dissection if axilla included in Rt
- If MT and 1-2 positive nodes: Axillary dissection or regional RT therapy
(AMAROS trial)

8. Tratamiento neoadyuvante: indicaciones - ventajas
Implications in the defining
the optimal extent of
surgical and RT regimens

9. Tratamiento quirúrgico: márgenes y V Axilar
After NST, optimal resection
is removal of residual as
opposed to original tumor
lesions with a
margin of “no ink on tumor”
regardless of unifocal
or multifocal disease
Exception:
IBC

10. Tratamiento quirúrgico: manejo de la axila y tto neoadyuvante
If > 3 sentinel nodes
identified and
negative
or if clipped node
and 1 or 2 additional nodes
removed and negative
Even if micromets
residual cancer
If cN2 at diagnosis:
- Axillary disection
- Regional nodal RT
(regardeless response
to NST)

11. Tratamiento RT adyuvante
Following breast conserving surgery, whole breast irradiation remains the standard
treatment recommendation for optimal outcomes
The Panel recommended hypofractionated radiation treatment schedules as preferred
for most patients after breast conservation [Whelan].
Two trials [RAPID, B-39]
- equally low risks of local recurrence in selected women with low-risk breast cancer undergoing
accelerated partial breast irradiation (APBI) compared with whole breast irradiation.
- Less favorable cosmetic outcomes were seen after APBI
- may be appropriate for carefully selected patients at low-risk of local recurrence

12. Tratamiento RT adyuvante: Elderly
Older women might avoid radiation therapy after breast conserving surgery for stage 1
breast cancer as randomized trials have shown that post-surgical radiation therapy does not
improve overall survival
The Panel tended to favor radiation after breast conserving surgery in
women age 70 who were otherwise in good health with substantial life-expectancy, as radiation therapy
meaningfully lowers the risk of in-breast recurrence.
However, the Panel recommended against radiation
in the “oldest” of the elderly, age 80 or greater

13. Tratamiento RT adyuvante: Regional Node Irradiation
RNI in cases of involvement of 4 or more axillary lymph nodes.
In cases of 1 to 3 positive lymph nodes, RNI in cases with adverse prognostic factors :
triple-negative, HER2, and luminal B cancers, and in women witihn residual disease after NST

14. Tratamiento RT adyuvante: post MT (PMRT)
Postmastectomy radiation therapy to the chest wall and regional lymph nodes in cases of 4 or more positive nodes,
or 1 to 3 positive nodes with triple-negative histology.
Discrepancies: HER2+, ER+ with 1-3 nodes, or T>5cm
NO recommended for T2N0
Same recommendations if inmmediate reconstruction (cosmesis impact)
After NST:
- PMRT if 1-3 residual nodes after NST
- in cT3cN0 triple negative breast cancer, even if pCR

15. Role of endocrine therapy in tumors with low ER expression (less than 10%)
- have a less favorable prognosis.
- most contemporary clinical trials involving endocrine therapy limit enrollment
to patients with tumors that are > 10% ER-positive.
- many trials for triple negative disease exclude patients with tumors that
have 1-10% staining ER staining.
- general consensus that the benefits of endocrine therapy are lower or possibly absent
when ER staining is 1-10%. However, without clinical data, the Panel could not identify a clear
threshold for withholding endocrine therapy and many panelists recommended adjuvant
endocrine therapy for tumors with > 1% ER expression [2].
Tratamiento adyuvante en ER+

16. Tratamiento adyuvante en ER+
Expert pathology RE, PR and
proliferation levels serves as a
surrogate for classification into more
favorable Luminal A vs B cancers;
however this assessments
lack robust validation
The Panel strongly endorsed the
value of genomic assays in T1/T2 N0
T3 N0, and TxN1 (1 to 3 positive LN).

17. Tratamiento adyuvante en ER+

18. Tratamiento adyuvante en HER2 + y TN

19. - The Panel recommended that tumor
infiltrating lymphocytes (TILs) be routinely characterized in triple negative breast cancer
(TNBC) because of their prognostic value. However, data are inadequate to recommend
TILs as a test to guide neo/adjuvant treatment choices in TNBC, as treatments are
largely governed by anatomic stage.
- Tumor PD-L1 or immune-cell PD-1 expression are
recognized as markers that may predict benefit from immunotherapy treatment in
advanced breast cancer. However, the Panel recommended against routine PD-L1
tumor or PD-1 immune cell testing in early stage TNBC, as current treatment algorithms
are not based on such testing
Tratamiento adyuvante en TN

21. Cáncer de mama precoz HER2+
> 2 cm y/o cN+ < 2 cm y cN0
NEOADYUVANCIA*
- FECx3 > Docetaxel + Trastu + Pertu x 3
- ACx4 > Taxol + Trastu + Pertu x 12 semanas
- Docetaxel + Carbo + Trastu + Pertu x 6
*Considerar Trastu + Pertu junto a antraciclinas y taxanos en tumores de alto riesgo
**El uso de Pertuzumab en Adyuvancia está autorizada por la EMA pendiente de financiación (P&R)
***pCR: ausencia de carcinoma infiltrante en mama y axila
CIRUGÍA
pT < 2 cm y pN0
ADYUVANCIA
Taxol x 12 + Trastu x18 ciclos
CIRUGÍA
no pCR*** pCR***
ADYUVANCIA
TDM1
pN+
cN0 al diagnóstico cN+ al diagnóstico
ADYUVANCIA
Trastu + Pertu** x total 18 ciclos
(más QT antras + taxanos si no neoadyuvancia)
ADYUVANCIA
Trastu x total 18 ciclos
Algoritmo de elaboración propi

23. ESMO 2019
Cáncer de mama

27. KEYNOTE-522: pCR by Key Patient
Subgroups
pCR, % (n/N)
Pembro +
CT
(n = 401)
Placebo + CT
(n = 201)
Δ (95% CI)
Disease stage IIA
IIB
IIIA
IIIB
73.1 (133/182)
56.2 (68/121)
66.7 (40/60)
48.6 (18/37)
62.1 (54/87)
48.4 (30/62)
42.1 (16/38)
23.1 (3/13)
11.0 (-0.7 to 23.2)
7.8 (-7.4 to 22.8)
24.6 (4.3 to 43.1)
25.6 (-6.1 to 48.9)
Lymph node
involvement
Negative
Positive
64.9 (124/191)
64.8 (136/210)
58.6 (58/99)
44.1 (45/102)
6.3 (-5.3 to 18.2)
20.6 (8.9 to 39.1)
PD-L1 expression CPS < 1
CPS ≥ 1
CPS ≥ 10
CPS ≥ 20
45.3 (29/64)
68.9 (230/334)
77.9 (162/208)
81.7 (103/126)
30.3 (10.33)
54.9 (90/164)
59.8 (55/92)
62.5 (40/64)
18.3 (-3.3 to 36.8)
14.2 (5.3 to 23.1)
17.5 (6.2 to 29.1)
18.5 (5.0 to 32.7)
Chemotherapy
exposure*
Full exposure
< Full exposure
69.7 (314/307)
51.1 (46/90)
55.3 (88/159)
35.7 (15/42)
14.4 (5.1 to 3.6)
15.4 (-3.0 to 32.1)
Schmid. SABCS 2019. Abstr GS3-03
*Full exposure comprised paclitaxel weekly 10-12 doses, carboplatin weekly 10-12 doses or Q3W 4
doses, doxorubicin or epirubicin Q3W 4 doses, and cyclophosphamide Q3W 4 doses, regardless of
exposure to pembrolizumab.

29. • Primary endpoint: IDFS
• Secondary endpoints: IDFS with second non-breast primary cancers included, DFS, OS, RFI, DRFI, safety
and HRQoL
• Stratification factors: Chemotherapy regimen, HR status, nodal status, geographic region, Protocol version
(A vs. B)
Chemotherapy* + trastuzumab
+ placebo (n=2405)
Chemotherapy* + trastuzumab
+ pertuzumab (n=2400)
Randomisation and treatment
within 8 weeks
of surgery
Anti-HER2 therapy for a total of 1 year (52 weeks)
(concurrent with start of taxane)
Radiotherapy and/or endocrine therapy may be
started at the end of adjuvant chemotherapy
Central
confirmation
of HER2
status
(N = 4805)
F
O
L
L
O
W
-
U
P
10
Y
E
A
R
S
R
S
U
R
G
E
R
Y
* Standard anthracycline or non-anthracycline (TCH) regimens were allowed
APHINITY
Von Minckwitz G, et al. N Engl J Med 2017; 377:122–131
DRFI, distant relapse-free interval; HRQoL, health-related quality of life;
RFI, relapse-free interval.

30. APHINITY: Clinical Benefit in Primary
vs Secondary Analysis
HR for IDFS (95% CI) Primary Analysis (mFU: 45.4 Mos) Updated Analysis (mFU: 74.1 Mos)
ITT population 0.81 (0.66-1.00) 0.76 (0.64-0.91)
Lymph node positive 0.77 (0.62-0.96) 0.72 (0.59-0.87)
Lymph node negative 1.13 (0.68-1.86) 1.02 (0.69-1.53)
Hormone receptor positive 0.86 (0.66-1.13) 0.73 (0.59-0.92)
Hormone receptor negative 0.76 (0.56-1.04) 0.83 (0.63-1.10)
IDFS at 6-Yr Pertuzumab, % Placebo, %
Absolute Benefit, % (95%
CI)
ITT population 90.6 87.8 2.8 (1.0-4.6)
Lymph node positive 87.9 83.4 4.5 (1.9-7.1)
Lymph node negative 95.0 94.9 0.1 (-2.0-2.2)
Hormone receptor positive 91.2 88.2 3.0 (0.8-5.2)
Hormone receptor negative 89.5 87.0 2.5 (-0.7-5.6)
Piccart. SABCS 2019. Abstr GS1-04

31. FeDeriCa: study design
Tan. SABCS 2019. Abstr PD4-07
Primary objective: Non-inferiority of the pre-dose cycle 8 P serum trough [ ] within PH FDC SC vs P IV
Secondary objectives: Non-inferiority of the pre-dose cycle 8 H serum trough [ ] , tpCR, safety

32. FeDeriCa: tpCR
Tan. SABCS 2019. Abstr PD4-07

33. • Open-label, randomized phase III trial
Atezolizumab 1200 mg Day 1 Q3W for 8 cycles +
Carboplatin AUC2 + nab-Paclitaxel 125 mg/m2
Day 1, Day 8 Q3W; 8 cycles
(n = 138)
NeoTRIPaPDL1: Study Design
Patients with HER2-/ER-
/PgR- early, high-risk
(T1cN1, T2N1, or T3N0)
or locally advanced
unilateral breast
cancer*
(N = 280)
Carboplatin AUC2 + nab-Paclitaxel (125 mg/m2)
Day 1, Day 8 Q3W; 8 cycles
(n = 142)
▪ Primary endpoint: EFS at 5 yrs after randomization of last patient
▪ Key secondary endpoint: pCR rate
▪ Other secondary endpoints: tolerability; predictive biomarkers
Gianni. SABCS 2019. Abstr GS3-04
Stratified by geographical area, disease stage
(early, high risk vs locally advanced), PD-L1
expression (positive IC vs negative)
*ER, PgR, HER2, and PD-L1 centrally assessed before randomization. Tumor and blood banked for
correlative studies.
Surgery
followed by
anthracycline
regimen x 4
cycles per
investigator
choice

34. NeoTRIPaPDL1: pCR Rate (ITT)
Overall pCR rate difference: 2.63%;
odds ratio: 1.11 (95% CI: 0.69-1.79);
P = .66
Gianni. SABCS 2019. Abstr GS3-04
Overall PD-L1 +ve PD-L1 -ve
60
50
40
30
20
10
0
43.5% 40.8% 51.9% 48.0% 32.2% 32.3%
Early, HR Locally Advanced
44.9% 39.7% 42.0% 42.0%
Carboplatin/nab-paclitaxel
Atezolizumab + carboplatin/
nab-paclitaxel

35. NSABP B-42: Study Design
Mamounas. Lancet Oncol. 2019;20(1):88. Mamounas. SABCS 2019. Abstr GS4-01
• Primary endpoint: DFS, second non-breast primary malignancy, or death from any cause (ITT)
• Secondary endpoints: OS, BCFI, distant recurrence, osteoporotic fractures, arterial thrombotic
events
Postmenopausal pts with
stage I-IIIA ER+ or PgR+
BC at diagnosis who
were disease free after 5
yrs of endocrine
therapy*
(N = 3966)
*Endocrine therapy defined as treatment with an
AI or tamoxifen for ≤ 3 yrs followed by an AI to
complete 5 yrs
Stratification for pathologic nodal status (negative vs
positive); prior adjuvant TAM (yes vs no); lowest BMD
T-score in spine, hip, or femur (> -2.0 to ≤ - 2.0 SD)
Letrozole 2.5 mg PO QD x 5
yrs (n = 1983)
Placebo x 5 yrs
(n = 1983)

36. NSABP B-42: DFS
Mamounas. SABCS 2019. Abstr GS4-01
Analy
sis
Events, N
HR (95%
CI)
P
Value*LET
PB
O
7 yrs 292 339
0.85
(0.73-
0.999)
.048
10 yrs 411 479
0.84
(0.74-
0.96)
.011
*Statistical significance level for
DFS set at .0418.
10-Yr DFSDFS(%)
Yrs After Randomization
PBO
LET
1.0
0.8
0.6
0.4
0.2
0.0
76.1
%
72.1
%
10
39
4
39
4
0
19
53
19
50
2
18
15
18
20
4
16
45
16
62
6
14
17
14
67
8
11
80
12
25

37. CORALLEEN: Study design
Postmenopausal
Stage II-III,
HR+/HER2-
and
PAM50 LumB
Letrozole + Ribociclib
TREATMENT
S
U
R
G
E
R
Y
PAM50
ROR-low
6 months
N=106
AC –> Paclitaxel
1:1
Week 2 biopsy
Gavilá. SABCS 2019. Abstr GS4-02

38. Chemotherapy
n= 52
Ribociclib + letrozole
n= 49
N (%) 95% CI N (%) 95% CI
ROR-low 24 (46.1%) 32.9-61.5 23 (46.9%) 32.5-61.7
ROR-intermediate 16 (30.8%) 19.1-45.9 15 (30.6%) 18.2-45.4
ROR-high 11 (21.2%) 11.2-35.2 11 (22.5%) 11.8-36.7
Missing 1 (1.9%) NA NA NA
Primary endpoint
This presentation is the intellectual property of the author/presenter. Contact them at jgavila@fivo.org for permission to reprint and/or distribute
San Antonio Breast Cancer Symposium®, December 10-14, 2019

39. San Antonio Breast Cancer Symposium®, December 10-14, 2019
Key secondary endpoints at surgery
This presentation is the intellectual property of the author/presenter. Contact them at jgavila@fivo.org for permission to reprint and/or distribute
Chemotherapy
n= 52
Ribociclib + letrozole
n= 49
N (%) 95% IC N (%) 95% IC
ROR score median (IQR) 25 (12.0-45.0) 18 (12.0-35.0)
Central Ki67 IHC median (IQR) 10 (3.0-20.0) 3 (1.0-8.0)
RCB 0-1 rate 6 (11.8%) 4.5-27.8 3 (6.1%) 1.3-16.8
pCR rate 3 (5.8%) 1.4-16.6 0 (0%) 0-7.2
PEPI
0 9 (17.3%) 8.6-31.4 11 (22.4%) 11.7-36.6
1-3 24 (46.1%) 33.6-62.6 25 (51.0%) 36.3-65.6
≥4 17 (32.7%) 21.2-48.7 13 (26.6%) 15.0-41.2
Missing 2 (3.9%) 0

40. Conclusiones
• Neoadyuvancia como biomarcador para seleccionar tratamiento adyuvante / grupos de riesgo
• Limitar la extensión de cirugía y RT
• Inmunoterapia en Ca mama precoz TN: controvertido
• Pertuzumab adyuvante: N+
• Nuevas formulaciones sc
• TDM1 tras neoadyuvancia (no pCR)
• Valor establecido de plataformas genómicas en enfermedad luminal
• Neoadyuvancia hormonal + CDKi como reemplazo de QT
• Adyuvancia hormonal extendida: seleccionar en grupos de riesgo (toxicidades/cumplimiento)