Download Locally advanced disease- Specific recommendations in systemic

Locally advanced diseaseSpecific recommendations in systemic
therapy
(ESO-ESMO ABC Guidelines and more…)
Alexandru ENIU, MD, PhD
Medical Oncologist
Department of Breast Tumors
Head, Day Hospital Unit
Cancer Institute Ion Chiricuţă
Cluj-Napoca, Romania
Heterogeneity of candidates for
neoadjuvant therapy
Stage
StageIIIB
IIIA
Locally Advanced- goal is to convert to operability
N0
N1
N1
T4
T3
StageN1IIB
N1
T4
Operable : goal is to conserve
the
breast
Stage IIIC
N0
N2
N3
T2 +T3
For the purpose
of this
N2 talk, LABC means INOPERABLE,
N2
T4
NON-METASTATICT1-3
LOCALLY ADVANCED BC
Locally advanced Breast Cancer
Heterogeneity at presentation: neglected versus rapidly
progressive disease
BREAST CANCER EPIDEMIOLOGY:
Stage at diagnosis: United States vs. India
DISTRIBUTION
USA
INDIA
STAGE
EXTENT
5 year
SURVIVAL
0
Noninvasiv
e
100%
16%
----
I
Early stage
disease
100%
40%
1%
II
Early stage
disease
86%
34%
23%
III
Locally
advanced
57%
6%
52%
IV
Metastatic
disease
20%
4%
24%
USA:
90% DCIS or
early staged
invasive disease
at diagnosis
INDIA:
76% locally
advanced or
metastatic at
diagnosis
Sources: SEER Survival Monograph (NCI), 2007;
Chopra, Cancer Institute Chennai, India, 2001
Neoadjuvant therapy
Paradigm shift: from LABC to “all tumors”
• Initially used to shrink inoperable cancers…
• Offers similar DFS and OS, vs. the same regimen
given as adjuvant treatment, same toxicity
Benefit seen in operable , large tumors
(downstaging)
Predictive: size, high grade, ductal, ERCollateral benefit: pCR patients survived longer!
Excellent in vivo experimental setting –FDA..
Few studies specifically in LABC ! !
The MD Anderson experience- LABC
pCR
Kuerer
4 x FAC
n=372
12%
Predictive
ER-, G3
Green (n=258)
4x q3wP
+
4 x FAC
15,7%
12 x wP
+
4 x FAC
28,2%
ER-, PR-
Kuerer, J Clin Oncol,1999; Green, J Clin Oncol 2005; Hennessy, J Clin Oncol 2005
Evaluation prior to primary systemic
therapy
 Clinical examination:
– Clinical size of tumor
– Skin changes: erythema, edema, ulceration, and
dimpling
– Lymph node status
 Photo documentation (inflammatory, T4’s…)
 Elicitation of symptoms suggestive for distant
metastasis
 Natural history of the disease (rapid growing <6
months versus neglected tumor to differentiate
T4d from T4b)
Evaluation prior to primary systemic
therapy (2)
BEFORE starting any therapy, a core biopsy providing histology and
 Pathology: CORE BIOPSY !
biomarker (ER, PR, HER-2, proliferation/grade) expression is
– Full assessment
of grade,decisions.
RE, RP and
(ki67)
indispensable
to guide treatment
(LoE:Her2
I B) (97%)
 Adequate breast imaging: extent of disease
– Mammography
– Ultrasound for T and N (FNA of suspicious nodes)
– MRI- if available for response assesment
– Clip
placement
dg (for
surgery &risk
pathology!)
Since
LABC
patientsathave
a significant
of metastatic disease, a full
staging workup, including a complete history, physical examination, lab
tests and imaging of chest and abdomen (preferably CT) and bone,
prior to initiation of systemic therapy is highly recommended.
(LoE: I B) (100%)
PET-CT, if available, may be used (instead of and not on top of CTs &
bone scan). (LoE: II B) (100%)
LOCALLY ADVANCED INOPERABLE BC (LABC)
Systemic therapy (not surgery or RT) should be the initial treatment.
If LABC remains inoperable after systemic therapy and eventual
radiation, “palliative” mastectomy should not be done, unless the
surgery is likely to result in an overall improvement in quality of life.
(LoE: Expert opinion) (100%)
A combined treatment modality based on a multidisciplinary approach
(systemic therapy, surgery and radiotherapy) is strongly indicated in the
vast majority of cases. (LoE: I A) (100%)
Triple Negative Breast Cancer
(ER-, PR-. Her2-, grade 3, high ki-67)
HETEROGENEITY
Basal - like
ER, PR,
Her2
Negative
“3-”
Infiltrating
ductal
carcinoma
Non Basal - like
Other histologies (medullary,
squamous, apocrine
Used as a surrogate to represent the basal-like
category ( ~80% of “3-” are basal-like)
Carboplatin in TNBC subgroup
of GEPARSIXTO
centrally
confirmed
TNBC
(RH<1%) R
T>1 cm (US)
or T>2cm
PM
100%
Correlate germline BRCA alterations and 80%
family history for breast and ovarian
60%
cancer with pCR in patients with TNBC
40%
20%
0%
Surgery
N=315
PMCb
Paclitaxel 80 mg/m² q1w
36
%
53
%
PM PMCb
Non-pegylated liposomal
doxorubicin (M)
20 mg/m² q1w
Carboplatin AUC 1.5-2 q1w
Bevacizumab 15 mg/kg q3w
Primary aim :pCR rates (ypT0 ypN0) rates between PM and PMC
von Minckwitz et al, J Clin Oncol 32:5s, 2014 (suppl; abstr 1005) and Lancet Oncology, May 2014
pCR (ypT0 ypN0)
in all Patients with TNBC
Family
history for BC/OC
gBRCA/RAD alteration
no
yes
(N=250)
(N=44)
40.4%
45.5%
(N=193)
(69/171)
(10/22)
yes
44.3%
63.6%
(N=101)
(35/79)
(14/22)
no
von Minckwitz et al, J Clin Oncol 32:5s, 2014 (suppl; abstr 1005)
Tumor-infiltrating lymphocytes are linked to chemotherapy response
and prognosis in breast cancer
40
Lymphocyte-predominant breast cancer (LPBC)
= more that 60% TILs
pCR rate (%)
40
30
20
15,4
7,2
10
0
no
focal
Lymphocyte
lymphocytes lymphocytes predominant
breast
Denkert et al, JCO, 2010
cancer
non-LPBC
Loi et al, JCO, 2013 – BIG2-98
Denkert et al, J Clin Oncol 32:5s, 2014 (suppl; abstr 510)
Metastasis-free
survival
•
•
•
•
Overall survival
278 TNBC patients
48% stage III ( LABC)
54% Node positive after neoadjuvant chemo
45% Anthra plus taxanesMetastasis-free
regimen survival,
Metastasis-free survival,
pN0, ypT<2 cm
pN+, ypT>2 cm
What have we learned?
 Carboplatin increases pCR in TNBC
 Best incremental benefit in patients with alteration
and family history( pCR rate 64%)
 Little gain from Carbo if no risk factors
 We are (almost) ready to incorporate Carbo in
neoadjuvant setting for TNBC (…adjuvant for
TNBC? Not yet…)
 15% of TNBC carry a BRCA alteration
 Immunological factors in breast cancer are linked
to response to neoadjuvant chemotherapy
LOCALLY ADVANCED INOPERABLE TNBC
Anthracycline- and-taxane-based chemotherapy is recommended as
initial treatment. (LoE: I A) (85%)
Response assessment
 Clinical exam at each cycle (T, N)-> to identify progression
 Post therapy: 2 weeks after last cycle of chemo
– Clinical exam: notoriously inaccurate!
– Mammography / ultrasound ( Chagpar, Ann Surg, 2006)
 MRI if performed at dg

better anatomic staging

limitations: false +, false - !
Clinical
utility?
 Functional Imaging (Dynamic Contrast Enhanced MRI,
PET)- still investigational
GEPARTRIO
Individualized therapy
“Her2 positive cc.”
 Her2 positive, ER - or +, PR – or +,
 High grade ( 3)
 High Ki-67
Gianni et al. Lancet 375(9714) , 2010
Can we improve the pCR? Dual HER2 Blockade
with Taxanes:NeoAltto and NeoSphere
LOCALLY ADVANCED INOPERABLE HER-2+
Concurrent taxane and anti-HER-2 therapy is recommended since it
increases the rate of pCR. (LoE: I A) (92%)
Anthracycline-based chemotherapy should be incorporated in the
treatment regimen. (LoE: I A) (72%)
When an anthracycline is given, it should be administered sequentially
with the anti-HER-2 therapy. (LoE: I A) (87%)
LOCALLY ADVANCED INOPERABLE HR+
Options for HR+ LABC include an anthracycline- and taxane-based
chemotherapy regimen, or endocrine therapy. (LoE: I A) (85%)
The choice of CT versus ET, as initial treatment, will depend on tumor
(grade, biomarker expression) and patient (menopausal status,
performance status, comorbidities, preference) considerations. (85%)
Primary hormonal therapy: luminal A
(ER +++, PR +++, Her2 -, Low Grade. Low ki-67)
Chemotheraphy versus Hormone Therapy as Neoadjuvant
Treatment in Luminal Breast Cancer: GEICAM 2006-03
In luminal phenotypes, chemotherapy induces more pCR than hormonal
therapy in the neoadjuvant setting
•
•
Chemotherapy appears to be more effective than hormonal therapy in patients with
Ki67 >10%, pre-menopausal and with high Allred score
Hormonal therapy appears to have similar efficacy to chemotherapy in patients with
Ki67 ≤10% and post-menopausal
Alba et al. ASCO 2010
Impact of pCR for luminal A tumors
pCR rate: 5,5% !
Preoperative Endocrine Therapy:
Conclusions
 Aromatase inhibitors more effective than TAM
 30-50% clinical response…but <5% pCR
 Breast conserv. in >40% initially proposed MRM
 Optimal duration: at least 4-6 mth (…12-18mths?)
 Not a substitute for surgery on the long term
 How to select?
– Postmenopausal patients ( no neoadj endocrine for
premenopausal patients)
– “true” Luminal A
– Ki-67 <10%??
Inflammatory breast cancer (IBC): introduction
5-year survival: 40%
Diagnosis is based on clinical presentation:

Erythema >30-50% of the breast, oedema, induration of the
breast, rapidly progressing disease ( history < 6 months)
Pathology findings:

Dermal lymphatic invasion, increased angiogenesis,
30–40% ErbB2+
Staging:



Imaging of thorax and abdomen recommended
Bone scan for patients with symptoms/elevated alkaline
phosphatase
Newer imaging modalities (FDG-PET) may be useful
By definition, inoperable at presentation
Mainstay of treatment: neoadjuvant chemotherapy
(6 cycles) with anthracyclines ± taxanes
FDG-PET; [18F]-fluorodeoxyglucose positron emission tomography
NOAH study results: pathological complete
response in ErbB2+ IBC
Pathological complete response (%)
(n=62)
80
p=0.004
55
60
40
20
0
19
Without T
Gianni et al. SABCS 2008;Abstract 31 and presentation
With T
INFLAMMATORY LABC
For inflammatory LABC, overall treatment recommendations are similar
to those for non-inflammatory LABC, with systemic therapy as first
treatment. (LoE: I B) (93%)
Mastectomy with axillary dissection is recommended in almost all cases,
even when there is good response to primary systemic therapy.
(LoE: I B) (95%)
Immediate reconstruction is generally not recommended in patients
with inflammatory LABC (LoE: Expert opinion) (95%)
Loco-regional radiotherapy (chest wall and lymph nodes) is required,
even when a pCR is achieved with systemic therapy. (LoE: I B) (98%)
LOCALLY ADVANCED INOPERABLE BC (LABC)
Following effective neoadjuvant systemic therapy with or without
radiotherapy, surgery will be possible in many patients.
This will consist of mastectomy with axillary dissection in the vast
majority of cases, but in selected patients with a good response, breast
conserving surgery may be possible. (LoE: II B) (98%)
Role of conservative surgery after
Neoadjuvant treatment?
• NeoALTTO: predictive factor: planned surgery
• Education of patients? Surgeons?
• Type of surgery
– Breast conserving surgery if appropriate
– MRM for all LABC ?!
– No“palliative” surgery if unresectable
• Criteria for breast conservation
( Singletary, Cancer Treat Res
1997)
–
–
–
–
–
Resolution of skin edema
Residual tumor size <5 cm
Absence of extensive breast lymphatic invasion
Absence of extensive suspicious microcalcifications
No evidence of multicentricity
Postoperative pathology report: what
do we need?
 pT ( number, location,
diameter)
 pN ( number of
positives/excised,
dim, extent of mets)
 Histologic type
 Grade
 Margin status (mm)
Symmans, J Clin Oncol 2007, 25:4414
 ER
 PR
 Her2
 Proliferation (Ki-67)
Systemic treatment after surgery
 Hormone receptor positive -> hormone therapy
 Her2 positive -> adjuvant trastuzumab
 Further chemotherapy ?
Would more chemotherapy
be better?
 Many (all?) patients had anthra+alkylator
and taxanes
Yes, tumor is really sensitive to chemo
 No data to suggest further
chemo
No, benefit
prognosisfrom
is already
very good
 In the absence of trial data, in general further
chemotherapy should not be administered if anthra
and taxanes have been already used
Would more chemotherapy be better?
Yes, high risk imposes further treatment
No, tumor does not respond to chemo
IBCSG Trial 22-00 (CM Maintenance)
Presented By Marco Colleoni at 2015 ASCO Annual Meeting
Slide 14
• 1 year CM maintenance is feasible with acceptable toxicity
• Alternative ( ..to nothing…) to be discusses with high risk
triple-negative patients willing to “invest”
Presented By Marco Colleoni at 2015 ASCO Annual Meeting
NEOADJUVANT SYSTEMIC THERAPY: UNSOLVED QUESTIONS
How to select CT versus HT in luminal tumors?
Optimal strategy for TNBC (platinum, PARPs)
Her2+ : who needs double blockade, and which one?
 Predictive markers for antiHer2 agents (PI3K ??)
 Do pCR patients need adjuvant anti-Her2 therapy?
Non-pCR patients: how to improve outcome?
Conclusions
 Anthra plus taxanes= standard backbone
 pCR is prognostic
 Endocrine neoadjuvant: for postm, “true”luminal A
 Anti-Her2 primary therapy: use trastuzumab!
 Recent approved indication for pertuzumab
(limited availability in Europe)
 Double anti-Her2 blockade: for ER-? PIK3CA wild?
 TNBC: anthra plus taxanes, discuss platinum(BRCA
mut. or family history):
 Immunological factors in breast cancer are
important- stay tuned!