Transcript Neoadjuvant therapy for breast cancer: the Stoddard protocol

Neoadjuvant therapy for breast
cancer: the Stoddard protocol
Scott D. Hamling, MD
General Surgeon
The Iowa Clinic
Objectives
• Patient eligibility
• Pretherapy evaluation
• Neoadjuvant systemic therapy (NAST)
options
• Treatment response monitoring
• Definitive surgical therapy
• Results
• The Stoddard protocol
Multidisciplinary Team Approach
Cases
• 48yo, cT4d cN2 cM0, grade 3, IDC, -, -, +.
• 60yo, cT3 cN1 cM0, grade 2, ILC, +, +, -.
• 39yo, cT2 cN0 cM0, grade 2, IDC, -, -, +.
• 37 yo, cT1c cN0 cM0, grade 3, IDC, -, -, -.
• 65 yo, cT3 cN0 cM0, grade 1, IDC, +, +, .
• Who would you offer NAST to?
48yo, cT4d cN2 cM0, grade 3, IDC,
ER-, PR-, Her 2+.
60yo, cT3 cN1 cM0, grade 2, ILC,
ER+, PR+, Her 2-.
39yo, cT2 cN0 cM0, grade 2, IDC,
ER-, PR-, Her 2 +.
37 yo, cT1c cN0 cM0, grade 3, IDC,
ER-, PR-, Her 2-.
65 yo, cT2 cN0 cM0, grade 1, IDC,
ER+, PR+, Her 2-.
NAST utilization: Stoddard registry
results
• 2013: 15/52 (29%) patients with
IBC/LABC were clearly documented as
having been offered/given NAST
– Most patients went straight to mastectomy
• 2013: 1/14 (7.1%) patients had
appropriate biospies, documented
complete pretherapy staging, and routine
image monitoring during NAST
NAST rational
• Systemic therapy intended to reduce the
risk of distant disease recurrence
• Improve surgical outcome when a primary
surgical resection is not possible or the
extent of resection is undersirable
• Allows in vivo treatment sensitivity
assessment
• Novel research window
Historical perspective
• Preoperative chemotherapy historically given to
•
patients with inflammatory and noninflammatory
unresectable LABC.
To summarize large and muture literature,
preoperative chemotherapy: (B-18, B-27)
– Capable of shrinking large primary tumors renduring
many inoperable patients operable
– Improves the survival of patients with IBC as part of
multimodality therapy, compared to locoregional
therapy alone
– Equivalent survival in operable breast cancer,
compared to adjuvant chemotherapy
Contemporary perspective
• Can NAST improve surgical outcomes in
patients with operable breast cancer?
– Increased rate of BCT
– Decreased extent of axillary surgery
• Can NAST allow tailored therapy to avoid
toxicities of ineffective therapy?
– Biologic monitoring of new drugs
– Neoadjuvant trials to avoid adjuvant trials
• Is NAST optimal for all patients?
Patient eligibility
• Surgical eligibility
– Unresectable disease: locally advanced breast
cancer (LABC), inflammatory breast cancer
(IBC)
– Resectable disease: if BCT is not possible or
cosmetic result is undesirable
– Contraindication to surgery at the time of
diagnosis: gestational breast cancer
Patient eligibility
• Tumor biology: NAST is most appropriate
in patients predicted to have a good
response
– Triple-negative breast cancer (TNBC)
– Her 2 positive breast cancer
Tumor biology
• TNBC:
– Pathologic complete response rate with NAST
27-45%, compared to 10% for HR pos, Her 2
neg breast cancer (Carey, 2007) (Esserman,
2012)
– Residual disease burden is predictive of early
distant recurrence and lower overall survival
(Liedtke, 2008)
Tumor biology
• Her 2 positive breast cancer
– I-SPY 1 trial (2012): T > 3cm, looked at pCR and
receptor status associations
• Relatively high pCR of 39% following treatment with
neoadjuvant chemotherapy (NACT) in Her 2 pos patients, vs
18% for Her 2 neg patients.
• Relatively high pCR rate regardless of HR status
– HR pos, Her 2 pos: pCR of 33%
– HR neg, Her 2 pos: pCR of 45%
• Significant increase in pCR to 60% in patients who also
received adjuvant Her 2 directed therapy.
– TECHNO trial (2011): Her 2 + patients receiving
NACT + traztusumab
• pCR rate was associated with improved disease free survival
(DFS) and overall survival (OS)
Pretherapy evaluation
• Complete histopathologic diagnosis
• Initial staging evaluation to rule out
distant metastatic disease
• Primary tumor evaluation
• Nodal evaluation
Diagnosis
• Pathologic evaluation
– Comprehensive histopathologic confirmation
– Hormone receptor status (ER/PR)
– Human epidermal growth factor receptor 2
status (Her 2)
Complete clinical staging
• Comprehensive clinical staging prior to
NAST, as surgical pathologic stage in
expected to be altered
– Exam
– Regional imaging and biopsies
– May include systemic scans to detect occult
distant disease, which would alter surgical
planning
Primary tumor evaluation
• Requires accurate radiopaque clip
placement to mark the tumor location
• Tumor size documentation
– Exam
– Imaging
• Mammogram
• US
• MRI
Nodal evaluation
• Negative axillary exam
– Axillary US with core needle biopsy (including
clip placement) of suspicious nodes detected
during imaging
– SLN bx pretherapy
• although posttherapy N stage has greater
prognostic significance
Nodal evaluation
• Positive axillary exam
– US core biopsy preferred
– Palpation FNA/core biopsy
• Consider SLN bx if discordant pathologic and
clinical results
– Clip placement is advised (esp if posttherapy
SLN bx is planned)
NAST
• Options
– Neoadjuvant chemotherapy (NACT)
– NACT with the incorporation of biologic
therapy (NACT + Her 2 directed therapy)
– Neoadjuvant hormonal therapy (NAHT)
• Limited data regarding the use of NAHT compared
to NACT
• NACT generally offered preferentially
– Recommendations based on tumor biology
NACT
• Patients receiving NACT have a statistically
higher likelihood of undergoing
cosmetically desirable surgery (B-18, 27)
• DFS and OS are equivalent, compared to
adjuvant systemic chemotherapy (B-18,
27)
– However, patients with a pCR at surgery have
a significant improvement in both DFS and
OS, compared to those with residual invasive
disease
NACT
• Regimen:
– Choice of systemic therapy is based on tumor
biology with similar efficacy expected to that
seen in the adjuvant setting.
• Timing:
– Since downstaging is the primary goal of
NAST, all planned NACT should be
administered prior to surgery.
• Provided no evidence of disease progression
NACT
• Anthracycline-taxane based regimens:
– Multiple studies have demonstrated increased
response rates in the neoadjuvant setting,
compared with non-taxane-containing
regimen (ex. NSABP B-27)
– ACT
– TC if contraindication to anthracycline
– May see carboplatin added to TNBC:
(GeparSixto, CALGB 40603, I-SPY 2)
NACT + Her 2 directed therapy
• Patients with Her 2 pos cancers have a
relatively high rate of pCR with NACT (ISPY 1)
• pCR increases with the addition of Her 2
directed therapy, esp if HR neg (I-SPY 2)
• pCR after NACT plus Her 2 directed
therapy is assoc. with recurrence and
survival advantages (TECHNO)
NACT + trastuzumab
• Benefit of adding Her 2 directed therapy
(NOAH trial):
– Improvement in pCR rate to 43% vs 20%
– Reduction in relapse rate to 26% vs 39%
– Trend to lower mortality rate of 13% vs 20%
– Increased benefit in both event free survival
and overall survival at 5 years compared to
NACT alone.
NACT + trastuzumab +
pertuzumab
• Pertuzumab (Perjeta)
– Monoclonal antibody that inhibits the
dimerization of Her 2 with other Her receptors
– Designed to overcome trastuzumab resistance
caused by the formation of Her 2:Her 3
heterodimers.
– NeoSphere and TRYPHAENA trials:
• Increased pCR with addition of pertuzumab to
trastuzumab
Neoadjuvant hormonal therapy
• Limited data in premenopausal women
• Often restricted to postmenopausal patients not
•
fit to receive or refuse NACT
Comparing NACT and NAHT(AI) in
postmenopausal stage II-III HR pos cancer
(Semiglazov et al, 2007):
– No differences in response rates
– Similar median time to observed response (57 vs 51
days)
– Similar pCR (3 vs 6%)
– Increased BCT rate with AI (33%) vs NACT (24%)
GEICAM study
– Randomized HR + cancers to NACT vs 24
weeks of exemestane (plus luteinizinghormone-releasing hormone analog goserelin
every 4 weeks in premenopausal patients)
• NACT patients had higher clinical response (66 vs
48%)
• pCR in 3 NACT patients, no pCR in NAHT
• Higher rate of BCT with NAHT (56 vs 47%)
• Lower grade 3 and 4 toxicities with NAHT (9 vs
47%)
NAHT drug of choice
• Postmenopausal patients: AI > TAM
– Letrozole vs tam: significantly higher overall
response rate (55 vs 36%) and BCT rate (45
vs 35%) (Ellis, 2007)
– PROACT study (Cataliotti, 2006): anastrozole
vs tam; no significant difference in overall
response rate (40 vs 35%), improved surgical
option rate (43% vs 31%)
• No preferred AI : (ACOSOG) Z1031 trial
– Exemestane, letrozole, anastrozole
Duration of NAHT
• Should be individualized to patients
• Response to therapy may not be evident
for 3 to 4 months and maximal response
may take longer
– Strobel et al (2008) found 62% response rate
by 4 months with AI for T2 or larger tumors
• Monitoring response to therapy to guide
surgical timing
Treatment response monitoring
• No formal guidelines exist
• NACT patients: exam prior to each cycle
of treatment
• NAHT patients: exam every 4-8 weeks
• Imaging:
– Midpoint of NAST and surgical scheduling
– If disease progression suspected
– MRI vs US depending on tumor and surgical
plan
Tumor monitoring
• MRI: (Yuan, 2010)
– highest specificity (91%) to predict pCR,
sensitivity low (63%)
– Sensitivity hampered by DCIS findings
• Chagpar, 2006:
– Accuracy of exam 66%, mammo 70%, US
75%
Response monitoring
• Correlation between tumor measurements
by PE, imaging, and final pathology are
modest at best
• Lack of concordance likely due to variable
patterns of tumor response
– Symmetric shrinkage around a residual
fibrotic scar vs residual cancer core
– Complete mass resolution despite the
persistence of microscopic foci
Surgical treatment
• Breast surgery
– Indications for surgical approach are similar to
patients who did not undergo NAST
– Definitive surgery should take place as soon
as the patient has recovered from NAST
toxicities (3-6 week window)
– NAHT patients do not need to cease
treatment prior to surgery
Surgical treatment
• Nodal evaluation following NAST:
– Clinically negative (cN0): outside of trial, sln
bx may be done prior to or after NAST. If
neg, no further axillary evaluation is required.
– Clinically positive (cN1/pN1):
• If remain clinically positive: ALND
• If convert to clinically negative:
– ALND
– Posttherapy sln bx if dual tracer used, at least two nodes
are recovered, and removal of prior biopsied node
confirmed by image confirmation of clip
SENTINA trial (2013)
• cN0 baseline: pre-NACT sln bx
– pN0: no further axillary eval
– pN1: post-NACT sln bx + ALND
• cN1 baseline: no pre-NACT bx
– cN0 post-NACT: sln bx + ALND
– cN1 post-NACT: ALND
SENTINA trial (2013)
• Results:
– In those who underwent a post-NACT sln bx
and ALND, patients who started out cN1 had
a higher sentinel node detection rate (80 vs
61%) and a lower FN rate (14 vs 52%)
compared to those who started out pN1
based on pre-NACT sln bx.
• Pre-NACT sln bx decreases success and accuracy
of post-NACT sln bx.
• NACT may adversely impact success of sln bx.
ACOSOG Z1071 trial (2012)
• Patients with cN1 disease at diagnosis
•
underwent sln bx and ALND after NACT.
Main results:
– Sln detection rate was 93%
– 41% of cN1 patients converted to pN0 after NACT
– FN rate in cN1 patients with at least 2 sln recovered
was 12.6% and dropped to 9.1% for 3 sln.
– FN rate lower with dual vs single agents (10.8 vs
20.3%)
– Confirmed findings NSABP B-27 (dual agent) and B32 (FN rate decreases with more sln recovered)
Adjuvant therapy
• Radiation therapy: XRT recommendation
typically based upon pretherapy clinical
staging
– BCT patients
– LABC and IBC patients s/p mastectomy
– Patients with post-NAST residual nodal
disease
NSABP B-51 trial
– Randomized phase III clinical trial evaluating
post-mastectomy chestwall and regional nodal
XRT and post-lumpectomy regional nodal XRT
in patients with positive axillary nodes before
NACT who convert pathologically to pN0 after
NACT.
Adjuvant therapy
• Adjuvant chemotherapy
– Typically not administer adjuvant chemo tx
– May consider adjuvant chemo tx if:
• Residual TNBC is present and their NACT did not
include both an anthracycline and a taxane.
• Patient treated with NAHT and is eligible for chemo
tx.
• Patient did not complete planned NACT course.
Adjuvant therapy
• Her 2 directed therapy:
– Resumption of trastuzumab to complete full
year course
– Initiation of trastuzumab if not part of their
NAST regimen
• Endocrine therapy:
– Recommended in HR positive patients
following locoregional treatment
Results
• CTNeoBC (2012)
– Patients with pCR had significant
improvement in EFS and OS
– The pCR rate varied by breast cancer subtype
• HR +, Her 2 -, grade 1-2: 7%
• HR +, Her 2 -, grade 3: 16%
• HR +, Her 2 + (NACT + trastuzumab): 30%
• HR -, Her 2 -: 34 %
• HR -, Her 2 + (NACT + trastuzumab): 50%
Working towards a central goal
The Stoddard Neoadjuvant Protocol
• Neoadjuvant therapy indications
– Absolute:
• Inflammatory breast cancer
• Locally advanced T3/T4 tumors, particularly if Her 2 positive
– Relative:
• Patients younger than 40 with tumors larger than 2 cm
regardless of nodal status
• Her 2 + (T2 or N1) to allow use of pertuzumab
• Stage II tumors not qualifying for de novo BCT
• N2/N3 disease, esp if hormone negative
The Stoddard Neoadjuvant Protocol
• Prior to starting neoadjuvant therapy:
– Clinically suspicious breast and nodal
abnormalities should be biopsied and marked
with radiopaque clips.
– Clinical and pathological staging should be
completed prior to starting therapy.
The Stoddard Neoadjuvant Protocol
• Imaging during NAST:
– Imaging at midpoint in therapy to assess response.
Exact timing will depend on regimen and treating
physicians.
– For women with baseline US clearly demonstrating
the tumor prior to NAST and choosing mastectomy,
repeat US utilized to monitor response.
– For women planning BCT after NAST, pre and postNAST MRI should be used to assess extent of
resection.
Cases
• 48yo, cT4d cN0 cM0, grade 3, IDC, +, -,
+.
• 60yo, cT3 cN1 cM0, grade 2, ILC, +, +, -.
• 39yo, cT2 cN0 cM0, grade 2, IDC, -, -, +.
• 37 yo, cT1c cN0 cM0, grade 3, IDC, -, -, -.
• 65 yo, cT2 cN0 cM0, grade 1, IDC, +, +, .
• Who would you offer NAST to?
Summary
• All patients who are candidates for systemic
•
•
•
•
therapy are candidates for NAST
If the indication for systemic therapy is
uncertain, then surgical therapy should be
completed first
NAST should be tailored to the biologic profile of
the tumor
Primary tumor and nodes must be measurable
and monitored
A multidisciplinary team approach must be
available