Adjuvant chemotherapy of breast
cancer
Presenter: Dr. Gita Bhat
Moderator: Dr. Linu Jacob
• Why adjuvant CT? (Rationale)
• What is the evidence for the benefit of adjuvant CT?
• Do all patients require adjuvant CT?
• How to select adjuvant systemic treatment?
• What adjuvant CT?
• When to start adjuvant CT?
• How many cycles of adjuvant CT?
• Toxicity of adjuvant CT?
• Special clinical situations
Why adjuvant CT?
• Fisher hypothesis
• Gompertzian model
• William S. Halsted
• Halsted radical mastectomy
• Breast cancer arose in one location and spread
to nearby lymph nodes and then throughout
the body
• So, removal of breast, chest wall muscle, and
lymph nodes was the logical treatment.
• Bernard Fisher - alternative
hypothesis
• “Breast cancer is a systemic disease
in that, tumor cells were likely to
have been disseminated throughout
the body by the time of diagnosis
and that more expansive
locoregional therapy was unlikely to
improve survival”
• In 1967, chairman of NSABP –
multicentre RCT
Fisher hypothesis :
“Breast cancer is considered a systemic disease at
time of diagnosis, a condition requiring treatment of
the entire patient rather than just the source organ”
Gompertzian model
• Benjamin Gompertz
• 18th century mathematician
“Law of mortality”
• Growth rate of populations are exponential at
early stages of development and slower at
later stages
150 years later….
Dr. Larry Norton
Norton and Simon hypothesis
• Tumors follow Gompertzian growth functions
• Smaller tumors grow faster than larger ones
• Rate of cell-killing by many drugs is proportional
to tumor growth rates
• Tumors given less time to regrow between
treatments are more likely to be destroyed
• Shorten the interval between chemotherapy
treatments from 3 weeks to 2
• High-density dosing – Improved survival
Dose dense chemotherapy
What is the evidence for benefit
of adjuvant CT?
EBCTCG meta-analysis
EBCTCG Meta-analysis
EBCTCG 2011
• Is there a benefit to adjuvant chemotherapy compared with
no treatment?
• Is there a benefit to anthracycline-based regimens compared
with CMF?
EBCTCG 2012
• Role of taxanes in adjuvant chemotherapy of early breast cancer
EBCTCG 2011
Compared with no treatment, the use of anthracycline-containing regimen
was associated with the following outcomes at 10 years:
Risk of recurrence
Significant
improvement
RR 0.73
Absolute gain of 8%
Breast cancer
mortality
Significant reduction
RR 0.79
Absolute gain of 6.5%
Overall mortality
Significant reduction
RR 0.84
Absolute gain of 5%
Compared with no treatment, the use of CMF was associated with these outcomes
at 10 years:
Risk of recurrence
Significant
improvement
RR 0.7
Absolute gain of
10.2%
Breast cancer
mortality
Significant reduction
RR 0.76
Absolute gain of 6.2%
Overall mortality
Significant reduction
RR 0.84
Absolute gain of 4.7%
Anthracycline-based therapy vs. CMF
The use of “standard” doses of anthracyclines was associated with the
following outcomes at 10 years compared with CMF (n=5122 women)
No improvement in the risk of recurrence (RR 0.99)
No improvement in breast cancer mortality (RR 0.98)
No improvement in overall mortality (RR 0.97)
The use of higher cumulative doses of anthracyclines (> 4 cycles, to
cumulative dose of >240 mg/m2) compared with CMF was associated with
the following outcomes at 10 years (n=9572)
Reduction in risk of
recurrence
RR 0.89
Absolute gain of 2.6%
Reduction in breast cancer
mortality
RR 0.80
Absolute gain of 4.1%
Reduction of overall
mortality
RR 0.84
Absolute gain of 3.9%
• Preference of anthracycline-containing
regimen as adjuvant chemotherapy
• Standard dosing of anthracycline-based
therapy is equivalent to CMF, though less
effective than more anthracycline-intensive
regimens
• However, the data did not take into account
the use of taxanes.
EBCTCG 2012 meta-analysis
Trials where the same control regimen was used in both arms (n=11,167
women) (8 year outcome):
Reduction in risk of
recurrence
RR 0.84
Absolute gain of 4.6% in RFS
Reduction in breast cancer
mortality
RR 0.86
2.8% improvement in breast
cancer-specific OS
Reduction in overall mortality
RR 0.86
3.2% improvement in OS
Trials where the number of cycles in the control anthracycline regimen was
doubled to mirror the addition of cycles of taxanes to anthracyclines
(n=33,084) (5 year outcome):
Reduction in risk of
recurrence
RR 0.86
Absolute gain of 2.9%
Reduction in breast cancer
mortality
RR 0.88
Absolute improvement of
1.4%
Reduction in overall
mortality
RR 0.9
Absolute improvement of
1.2%
• Affirms the benefit of taxanes when
incorporated into the adjuvant setting for
women with newly-diagnosed breast cancer
• The benefits were seen independent of age,
nodal status, tumor size, tumor grade and ER
status
Do all patients require adjuvant CT?
How to select adjuvant systemic treatment?
St. Gallen Consensus
Conference 2013
National Comprehensive
Cancer Network 2013
HER2 positive tumors
Adjuvant chemotherapy (no
specific size threshold) and
trastuzumab
Adjuvant chemotherapy and
trastuzumab for tumors >0.5 cm
and/or node-positive
HER2 negative tumors
ER negative:
Adjuvant chemotherapy (no
specific size threshold)
ER negative:
Adjuvant chemotherapy for tumors
≥ 1.0 cm and/or node positive
Consider for tumors 0.5 to 1.0 cm if
adverse prognostic factors are
present (lymphovascular invasion,
high-grade features)
HER2 negative tumors
ER positive:
Adjuvant chemotherapy if 4 or ore
lymph nodes are positive
Consider if tumor >2 cm, or grade
2-3, or age <35, or lymphovascular
invasion is present.
Risk stratify by
ER/PR/Ki67/Oncotype Dx/ Intrinsic
subtype
ER positive:
Adjuvant chemotherapy if nodepositive
Risk stratify by Oncotype Dx if node
negative (and in select patients
with 1-3 involved ipsilateral axillary
LN – NCCN 2015)
Consider if tumor >1 cm, or if
tumor 0.6 to 1.0 cm and
lymphovascular invasion or grade
2-3 features are present.
Systemic treatment for early breast
cancer subtypes
Subtype
Recommended therapy
Luminal A-like
ET alone in the majority of cases
Consider CT if
i) High tumor burden (four or more
positive lymph nodes, T3, or
higher)
ii) Grade III
Luminal B-like (HER 2-negative)
ET+CT for the majority of the cases
Luminal B-like (HER2-positive)
CT+ anti-HER2+ ET for all the patients
HER2-positive (non-luminal)
CT+ anti-HER2
Triple-negative (ductal)
CT
• * For special histological subtypes:
• St. Gallen 2013 recommendations
ET for endocrine responsive
CT for endocrine non-responsive
Cribriform
Apocrine
Tubular
Medullary
Mucinous
Adenoid cystic
Metaplastic
Do all patients require adjuvant chemotherapy?
• Previously: Based on T size and N status
• Now: Tumor biology (Prognosis and variable response to
chemotherapy)
• IBCSG and CALGB:
• Some HR+ breast cancers do not benefit from adjuvant
CT and are relatively chemo resistant. They have
excellent prognosis with endocrine treatment alone.
• * Post menopausal ER+, LN• Therefore, role of genomics to help us select patients for
CT
Tools to select patients
•
•
•
•
•
Oncotype Dx
Mammaprint
Adjuvant! Online
NPI
Predict score
Oncotype Dx or RS assay for patients with ER+, LN- disease:
• 16 cancer and 5 reference genes from 3 studies:
Category
RS 0-100
Low risk
RS <18
Intermediate risk
RS ≥18 to ≤31
High risk
RS ≥ 31
• Clinical validation – B14 results
• Patients with tumors that have low RS derive minimal if any benefit from CT
• Patients with tumors that have high RS have a large absolute benefit from CT
NCI Cooperative Groups TAILORx
Node-Negative, ER-Positive Breast Cancer
Register
Specimen
banking
21-Gene Recurrence
Score Assay
RS 11-25
Recurrence
Score <10
Hormone
Therapy
Registry
Randomize
Hormone Rx
vs
Chemotherapy +
Hormone Rx
Primary study group
RS >25
Chemotherapy
+
Hormone Rx
• Primary study group: Those with RS between 11 and 25 will be
randomized to either hormonal therapy alone or hormonal therapy
+ chemotherapy.
• This corresponds approximately to a risk of recurrence at 10 years
of 10%-20%.
• Dealer’s choice–type design: Individual investigators can select the
type of hormonal therapy and chemotherapy from a list included in
the protocol.
• The groups do not correspond to the low-, intermediate and highrisk cutoffs found on the Oncotype DX™ report.
• The cutoffs in the study were selected to correspond with specific
risk levels.
• It was felt that it was not ethical to deprive a women of
chemotherapy if she had a risk level above 20%.
RxPONDER
• Rx for Positive node, Endocrine Responsive
Breast Cancer trial
• Use of 21-gene RS in node positive population
Other molecular tools for deciding
chemotherapy in node negative patients:
•






70-gene signature (Mammaprint):
It uses fresh tissue for microarray analysis
US FDA approval in February 2007
LN negative patients of all ages, ER negative or positive, with tumor size <5 cm
MINDACT trial: phase III RCT
Mammaprint vs. Adjuvant!Online
Selecting patients who are LN negative or 1-3 LN+ for adjuvant chemotherapy in
breast cancer
•
•
PAM50 intrinsic subtype classifier
GGI- Gene Expression Grade Index ( 97-gene measure of histologic grade. High
GGI is associated with a lower relapse-free survival)
• NPI: Nottingham Prognostic Index
• Prognostic scoring system for EBC
• Divides patients into 6 prognostic groups
based on tumor size, grade and lymph node
status
• PREDICT: UK prognostic model that predicts
survival following surgery for invasive breast
cancer
• Adjuvant! Online: Web based tool to estimate
the net benefit of adjuvant treatment for an
individual patient
• Estimates prognosis based on tumor size,
number of involved LN, grading, ER status
• Source: SEER database
• Assessment of treatment effect is mainly
based on: EBCTCG overview meta-analysis
What adjuvant CT?
• EBCTCG meta-analysis: benefit of
polychemotherapy, anthracyclines and
taxanes
• Evolution through CMF, AC, FAC and FEC-D
• Concurrent anthracycline-taxane vs sequential
• Weekly vs 3 weekly taxane
• Role of dose dense CT
• Role of HDCT
History (NSABP trials)
•
•
B-01 (1958-61)
– Thiotepa vs placebo. Short course perioperative. Advantage in premenopausal, >4
nodes positive
B-05 (1972-75)
– L-PAM (L-phenylalanine mustard, Melphalan) for node-positive orally for 2 year. 8%
DFS and 5% OS advantage in < 50 years at 10 year follow up
•
B-10 (1977-81)- immunotherapy
– Combination chemotherapy (L-PAM + 5FU) +/- C.parvum and hydrocortisone: no
adv
•
B-11 (1981-84)
– {L-PAM + 5-FU} +/- Adriamycin for node-positive and ER-negative tumors
•
B-13 (1981-88)
– chemotherapy (sequential MTX and 5-FU) for node-negative, ER-negative tumors
– Benefit at 8 yr in overall DFS (74% v 59%; P < .001) was seen
Adjuvant treatment and survival improvement
over the past 40 years
CMF
• Cyclophosphamide, methotrexate and 5-FU
• 1st regimen to show improved DFS and OS in adjuvant
treatment of breast cancer
• Well tolerated
ADR: Fatigue, nausea and diarrhea
• Use has diminished with data showing benefit of
anthracyclines
CMF PO (Classic CMF)
Cyclophosphamide 100mg/m2 po d1-d14
Methotrexate 40 mg/m2 iv d1 and d8
5-FU 600mg/m2 iv d1 and d8
CMF iv
C 600mg/m2 iv d1
M 40mg/m2 iv d1 and d8
F 600mg/m2 iv d1
Epirubicin---CMF
Epirubicin 100 mg/m2 iv q3w* 4 cycles
Followed by CMF* 4 cycles
N=2391, N+ and NRFS of ECMF 83% vs 77%
OS 88% vs 82%
AC
• NSABP-B-15 (1984-88)
• AC*4=CMF*6
•
•
•
•
Findings from 2,194 patients indicate no significant difference in disease-free
survival (DFS, P = .5), distant disease-free survival (DDFS, P = .5) or survival (S, P =
.8) among the three groups
AC seems preferable since: AC was completed on day 63 versus day 154 for
conventional CMF
patients visited health professionals three times as often for conventional CMF as
for AC
nausea-control medication was given for about 84 days to conventional CMF
patients versus for about 12 days to patients on AC.
FAC
SECSG Trial in Node-Positive Breast Cancer:
Median follow-up of 5 years (n = 528):
• No significant difference in overall survival rates (74% vs 68%, P = .415)
between CAF and CMF
• Major toxicities similar
SWOG BREAST INTERGROUP INT0102 TRIAL: CMF vs FAC, in node negative
EBC
• 10-year estimates indicated that CAF was not significantly better than CMF
for DFS (77% v 75%; HR 1.09; 95% CI, 0.94 to 1.27).
• CAF had slightly better OS than CMF (85% v 82%, HR 1.19 for CMF v CAF;
95% CI, 0.99 to 1.43)
• Toxicity was greater with CAF
Role of anthracyclines (contd…)
• EBCTCG 2011 meta-analysis
• What is the optimal dose?
• CALGB 9344: compared 60/75/90 mg/m2 of Adriamycin – no benefit of
dose escalation
• CALGB 8541: Evaluated 3 doses of anthracyclines – low (30mg/m2),
moderate (40 mg/m2) and high (60 mg/m2). Benefit with high dose in OS
and RFS in HER2 positive patients.
Epirubicin – What is the optimal dose?
• 1996: ICCG
• Showed that FEC 50 and CMF had similar efficacy in premenopausal, node-positive patients
• 1998: Dose of Epirubicin (FASG)
• FEC-100 vs FEC-50 as adjuvant treatment for patients with
Node-positive breast cancer
• 5-yr RFS 65% vs 52% (Relative risk reduction 32% P= 0.007)
• 5-yr OS 76% vs 65% (Relative risk reduction 31% P=0.007)
• CHF/AML/ALL – (1.1%, 0.4%, 0) vs (0.4%, 0, 0.4%)
Role of taxanes
EBCTCG 2012
CALGB 9344
N >3,000 patients
A: 60=75=90 mg/m2
5-year DFS
65% vs 70%
P= 0.0023
P 175 mg/m2
5-year OS
77% vs 80%
P= 0.0064
C:600 mg/m2
PACS 01 trial: FEC-D
S
U
R
G
E
R
Y
6 * FEC100: Arm A
5-FU
500mg/m2 on day 1
Epirubicin
100mg/m2 on day 1
Cyclophosphamide 500mg/m2 on day 1
6 cycles (q3w)
R
FEC-D: Arm B
3 cycles of FEC 100 q21 days
followed by
3 cycles of Docetaxel 100 mg/m2 on day 1
Every 21 days
Stratified on:
Centre
Age: < or ≥ 50y
Nodes: 1-3; ≥4
Key outcomes of PACS-01
• FEC-D
• Superior DFS and OS irrespective of number of nodes or
hormonal status
• 18% reduction in risk of relapse
• 23% reduction in risk of death
• Significant DFS benefit with FEC-D in ≥ 50 years age group
(P= 0.001)
• Incidence of FN with FEC-D: 11.2% (vs 24.7% with TAC)
• Reduced risks of acute and delayed cardiac events because
of 50% less exposure to anthracyclines
• FEC-D is a reasonable alternative in patients ≥ 50 years of
age.
Role of Taxane-based combinations as adjuvant
chemotherapy of early breast cancer
Concurrent vs sequential
BCIRG 005
NSABP-B-30
BCIRG 005
• Phase III RCT
• TAC (6) vs. AC (4) ---T (4)
• EBC – HER2 normal and
axillary LN positive
BCIRG 005 study design
Primary EP: DFS
Secondary EP:
OS, safety
Major eligibility criteria:
•HER2 normal by central FISH
•Histologically proven node-positive
•Stage T1-3, N1, M0
•Age ≤ 70 years, KPS ≥ 80%
BCIRG 005
BCIRG 005
Non-hematological adverse events (Grade 3 or 4 with incidence >1%)
TAC
N= 1635
AC-T
N= 1634
%
%
P-value
Arthralgia
0.9
2.4
0.001
Sensory
neuropathy
0.3
1.5
0.0004
Fluid retention
1.3
2.8
0.011
HFS
0
1.8
<0.0001
Myalgia
0.9
4.9
<0.0001
Key findings of BCIRG 005
• For the primary endpoint, DFS, adjuvant TAC is equivalent
to AC-T in patients with HER2 normal, node positive breast
cancer
• Despite AC-T delivering higher dose intensity for each of
the three agents and requiring 8 cycles, AC-T was not more
effective than TAC
• Compared to AC-T, TAC is associated with:
 More febrile neutropenia and GCSF use.
 Less sensory neuropathy, nail change, myalgia and shorter
duration of therapy
NSABP-B-30
• 1999-2004
• Role of sequential vs concurrent taxanes
• 3 arms (AC*4—T*4) vs (AT*4) vs (TAC*4)
AC-T
AT
TAC
8 yr DFS
74%
68%
69%
8 yr OS
83%
79%
79%
“Sequential better than concurrent and AT noninferior to TAC”
BCIRG 001
•
•
•
•
•
TAC vs FAC
1491 patients, Node+
Median follow up: 124 months
DFS: 62% (TAC) vs 55% (FAC) (P=0.0043)
10Y OS: 76% (TAC) vs 69% (FAC) (p=0.0002)
CALGB-9741 (contd..)
Key findings of CALGB 9741
• At 4 yr: 26% reduction in risk of recurrence
and 31% improvement in OS with dose-dense
administration.
• There was a significant improvement in DFS
for dose dense regimen 82 vs 75%
• OS also improved(92 vs 90)
• Dose density improved DFS and OS, no
difference was seen between sequential or
concurrent schedule
10-year follow up of Intense Dose-dense
chemotherapy vs. Conventional chemotherapy in
high-risk patients with ≥4 positive LNs (SABCS 2012)
• Rationale: There are no published reports of longterm survival and toxicity data with dose-sense
regimens.
• Objective: Confirm the Norton Simon hypothesis
of dose density and evaluate the safety of
epoietin alfa as primary prophylaxis
• Study population: High-risk patients having
atleast 4 positive LN
• All patients in the dose-dense arm received G-CSF
Epirubicin
150mg/m2
q2w*3
Paclitaxel 225
mg/m2
q2w*3
Cyclophosphamide
2500 mg/m2
q2w*3
N=1284
+TAM
R
A
N
D
O
M
I
Z
E
G-CSF ± epoietin alfa
+TAM
EC 90/600 mg/m2
q3w*4
Paclitaxel 175 mg/m2
q3w*4
Primary EP: RFS
Secondary EP:
OS, QOL, toxicity
• Efficacy results:
Outcome
IDD-ETC
EC→T
HR (95% CI)
P-value
10-yr RFS
56%
47%
0.74 (0.63-0.87)
.00014
10-yr OS
4-9 positive LNs
10+ positive LNs
69%
74%
62%
59%
66%
48%
0.72 (0.60-0.87)
0.77 (0.59-1.01)
0.66 (0.51-0.86)
.0007
.06
.0016
• No therapy-related death or long-term toxicity was observed
with iddETC
• Transfusion results:
• Negative impacts of epoietin alfa on RFS and OS were not
observed
Transfusion-related outcomes
Median hemoglobin (g/dL)
• ;
Need
for ≥1 transfusion
Patients with venous thrombotic
event
IDD-ETC
(n=324)
IDD-ETC +
EPO
(n=319)
--
--
< .001 (favoring +EPO
arm)
28%
13%
< .0001
7%
13%
.029
P-value
Node-negative breast cancer
• GEICAM 9805 (FAC vs. TAC)
significant toxicity
• GEICAM/2003-02 (FAC vs. FAC—wP)
GEICAM 9805 (FAC vs TAC)
• High-risk, node-negative breast cancer defined
according to St. Gallen criteria
•18-70 years
•Post primary surgery
for unilateral operable
breast cancer (T1-T3,
N0)
•≥1 of St. Gallen 1998
high risk criteria:
T size > 2cm
ER and PR negative
Tumor Grade II or III
Age <35 y
TAC q3w*6 cycles
Randomized
FAC q3w*6 cycles
Primary EP: DFS
Sec EP: OS
Results of GEICAM 9805
•
•
•
•
At a median follow-up of 77 months:
TAC group had 32% reduction in the risk of having an event
Fewer local and distant relapses
Estimated DFS at 5 years: 90.1% in TAC group vs. 85.3% in
FAC group
• 24% reduction in the risk of death among those who
received TAC
• Safety: Grade 3 or 4 ADR (TAC> FAC) – asthenia,
neutropenia and leucopenia
• All grades (TAC> FAC) – Peripheral motor neuropathy,
sensory neuropathy, one pain, pyrexia, skin changes,
peripheral edema, arthralgia, amenorrhea and myalgia
Key findings of GEICAM 9805
• In women with high risk, node negative breast
cancer:
• TAC significantly improved DFS (32% reduction in
risk of recurrence at 77 months)
• Benefit from TAC maybe due to hormonal effect
in pre-menopausal women (Chemotherapy
induced amenorrhea: TAC> FAC)
• Post menopausal women also derived benefit
from TAC
GEICAM/2003-02 study
• Node negative breast cancer with high risk of
recurrence as per St. Gallen criteria
• FAC (6) vs. FAC (4)---wP(8)
• Primary EP: DFS
• Secondary P: OS
GEICAM/2003-02 (contd…)
•
•
•
•
Results:
At a median follow-up of 63.3 months:
5Y-DFS: 93% in FAC-wP vs 90.3% in FAC
FAC-wP reduces the risk of relapse by 26.7% compared with FAC (statistically sig.)
FAC-wP
FAC
Grade 3-4 neutropenia
21.8%
25.4%
Febrile neutropenia
2.7%
3.6%
Fatigue
7.9%
3.4%
Sensory neuropathy
5.5%
0
Vomiting
4.3%
4.1%
Persistent amenorrhea
15.9%
10.6%
Higher incidence of thrombosis with FAC-wP (due to use of steroids)
AC vs AC--P
• CALGB 9344: 5y DFS 65% vs 70%
•
OS: 77% vs 80%
• NSABP-B-28: 5y DFS:72% vs 76%
•
OS: 85% vs 85%
Which regimen?
• As of today, there are no recommendations
for choosing the regimen based on
Histopathology or Intrinsic subtypes.
• Choice of chemotherapy is based on
comorbidities, side effects and patient
preference.
• Endocrine-responsive breast cancer
• HER2 positive breast cancer
• TNBC
* Adjuvant chemotherapy: Which patient? What regimen? (ASCO
2013 Educational book)
Endocrine-responsive breast cancer
• Luminal A: Node negative- no benefit from
adjuvant CT
• Node positive:
• ? Absolute benefit of CT
• Addition of CT to be discussed with the
patient
• Luminal B: High Ki67 index, aggressive, risk of relapse
• Hence, chemotherapy and endocrine therapy are
indicated
• Choice of CT is based on risk of relapse
Luminal B with additional risk
factors: pT>1 &/or pN>0
Luminal B without additional
high risk factors
Sequential anthracyclinesTaxanes
Docetaxel/cyclophosphamide
Adriamycin/cyclophosphamide
CMF
Spares toxicity
Does not compromise efficacy
HER-2 positive breast cancer:
• Trastuzumab + Chemotherapy
• Major consideration: Whether or not to add
an anthracycline
• Observed increased sensitivity of HER2+
tumors to anthracyclines is due to TOP2A
amplification
BCIRG 006
• Phase III trial comparing AC → T with AC →
TH and with TCH in the adjuvant treatment of
HER2-amplified early breast cancer patients:
Third planned efficacy analysis
• (Slamon et al, SABCS 2009)
BCIRG 006 (contd..)
• Trastuzumab provides a similar and significant
advantage for both DFS and OS when used
with either ACTH or TCH.
• The acute and chronic toxicity profiles of TCH
are better than those of ACTH
• No statistically significant advantage of ACTH
over TCH
• CHF was 5* more in ACTH than in TCH
• Plan treatment based on risk of relapse:
HER2 positive EBC with high
risk features (pT >1 and/or
pN>0)
AC-TH
HER2 positive EBC with low
risk features
TCH
TNBC
• TNBC with good prognosis:
• Adenoid cystic and medullary
N-
Avoid adjuvant
CT
N+
Give adjuvant CT even
with good prognosis
subtype
• Other TNBC:
• Eg: Metaplastic
• Adjuvant CT: Sequential anthracyclines –
taxane regimen
• TNBC and BRCA-associated breast cancer:
• Use of platinum
When to start adjuvant CT?
• Preferably within 2 to 6 weeks
• Significant decrease in the efficacy of
chemotherapy is observed when administered
more than 12 weeks from surgery
How many cycles of adjuvant CT?
• 6-8 cycles
Early and late long-term effects of
adjuvant chemotherapy in breast cancer
*Breast cancer - ASCO 2013 educational book
• Adjuvant CT can lead to early and late long-term
side effects for breast cancer survivors.
• Effects of CT can vary in severity, but can often
negatively affect the QOL and overall health
status.
• Screening for symptoms, use of supportive
medication, referral for specialty consultation as
needed
• Ongoing research: Evaluate the etiology of
toxicity as well as effective interventions
Ovarian failure: premature Hot flashes
menopause, infertility,
Atrophic vaginitis
sexual dysfunction
Loss of pelvic muscle tone
Loss of libido
Pretherapy referral to a
fertility specialist
Assisted reproduction
(Ovarian stimulation with
AI in the setting of HR+
cancer)
Weight gain
Reasons: changes in
activity level, menopausal
status, endocrine
manipulation, diet,
metabolism and mood
Nurses’ Health Study:
Weight gain may increase
the risk of recurrence
Diet
Exercise
Active lifestyle
Bone loss
Premature menopause
Effect of AI
WHI study: increased risk
of fracture in post
menopausal breast cancer
survivors
Screen at risk individuals:
DEXA q1-2y
Timely initiation of
bisphosphonates
Adequate calcium and
Vitamin D
Weight bearing exercise
Neuropathy:
• Peripheral sensory and motor neuropathy –
affect QOL
• Microtubule inhibitors: Taxanes
• Rate and severity of taxane-related
neuropathy: agent selection, dose, schedule,
comorbidities
•
•
•
•
•
Supportive management:
Dose modification and treatment delay
Glutathione, acetyl-l-carnitine, alpha-lipoic acid
Gabapentin, venlafaxine
CALGB 170601: Duloxetine for painful chemotherapy-induced
neuropathy
• Best management: Avoid toxicity by identification of individuals at
highest risk
 Higher P-APS scores with first dose of CT may correlate with
peripheral neuropathy
 Identification of SNPs associated with development of moderate to
severe peripheral neuropathy after paclitaxel exposure
• * Taxol package insert
• Severity is dose dependent
• Those with pre-existing neuropathy should be
carefully monitored
• In severe cases, all subsequent doses of
paclitaxel should be reduced by 20%
• Cardiac dysfunction:
• Left ventricular dysfunction (Anthracyclines and
trastuzumab > cyclophosphamide and taxanes)
• Prechemotherapy identification of individuals at
high risk of toxicity: Older age, pre-existing
hypertension, low baseline LVEF, elevated BMI
• Cardiac risk score (Age and LVEF) to predict the
risk of a cardiac event (NSABP-B-31)
• ECHO
• Anthracycline mediated cardiotoxicity:
• Late-onset (atleast I year after completion of
CT) > acute or sub-acute
• Permanent cardiomyocyte apoptosis and
necrosis
• Late onset: irreversible, related to cumulative
anthracycline dose, due to free radical
formation
• Rates of symptomatic or severe cardiac
dysfunction in the major trials of adjuvant
trastuzumab + anthracycline: maximum of 4.1%
• Trastuzumab without chemotherapy/ T without
anthracyclines: 0.6% to 1.87%
• Rates of asymptomatic drop in cardiac function
after anthracycline exposure: 17% to 19%
• Neurocognitive dysfunction:
• “Chemo brain”
• 75% of women: change in cognitive function 2y after
treatment (attention, memory and concentration)
• Multifactorial: exposure to CT, other modalities of
treatment, supportive care medications, menopausal
symptoms, anxiety, depression, fatigue, comorbidities
• Role of genetic polymorphisms: APOE and COMT
• ? Prophylactic or therapeutic modafinil, fluoxetine, CBT
• Secondary malignancy:
•
•
•
Rare yet most feared complication – MDS or AML
<1% ( reflect increased cumulative dose)
Concurrent use of growth factors, RT
Alkylators
Topoisomerase-II targeted
agents
Examples
Cyclophosphamide
Anthracyclines
Induction period
5-8 y after start of therapy
2-3 y
Preceded by MDS
yes
No
Type of translocation
Unbalanced
Balanced
Chromosomes involved
Long arm del or monosomy
of chr 5 and 7
MLL, RARA, RUNX1 loci of
11q23, 17q21, 21q22
Special situations
• Very young patient (< 35 years)
• Older patients (≥ 65 years)
• Isolated local and regional recurrence
Very young patient (<35 years)
• Young age is an independent risk factor for poor
prognosis
• Aggressive disease: high incidence of
 Hormone insensitive
 Undifferentiated
 HER2+ tumors
• Combination chemotherapy with anthracyclines and
taxanes: Luminal B, HER2+, TNBC; even for N• Gonadal toxicity
• Early referral to reproductive specialist
Chemotherapy in older patients (≥ 65 years)
•
•
•
•
•
Comprehensive geriatric assessment
Balance against:
Risk of toxicity
Poor QOL
Functional decline
• Combination CT preferred in
 Node+, HR- EBC
 HR+, Luminal B
 HR-, Node-
Polychemotherapy in older patient?
CALGB 49907
RFS
Age > 65y
60% ≥ 70
R
A
N
D
O
M
I
Z
E
Oral CMF * 6
AC * 4
Capecitabine (X)
* 6 cycles
Both arms were tolerated well but more toxicity in
AC/CMF
Median follow-up: 2-4 years
CMF/AC vs single agent Capecitabine: Better RFS (p=0.00009)
Difference particularly marked in ER negative
Polychemotherapy is relevant in the elderly population
CALOR: Adjuvant CT for ILRR (SABCS 2012)
• Rationale: isolated local or regional recurrence
(ILRR) of breast cancer has poor prognosis
• No randomized studies of adjuvant
chemotherapy for ILRR have been published in
the last 30 years
• Objective: Evaluate the effect of adjuvant
chemotherapy on patients with ILRR
• Sample size: Original 977
• Due to slow accrual, only 162 patients were
randomized
CALOR trial (contd..)
R
A
N
D
O
M
I
Z
E
Adjuvant
chemotherapy
+Endocrine therapy
for HR-positive
disease
+ HER2-directed
therapy (optional)
No
chemotherapy
+ RT (mandatory for
those with positive
margins)
• Chemotherapy chosen by investigators
• At least 2 drugs, 3-6 months of therapy
Eligibility criteria:
•First ILRR
•Complete gross excision
of recurrence
•No evidence of positive
SCLN
•No evidence of distant
metastasis
CALOR trial (contd..)
• Results:
Chemotherap
y*
(n=85)
No
chemotherapy*
(n=77)
Total failures
24
34
Local/regional
6 (25%)
9 (26%)
Distant
Soft tissue
Bone
Viscera
15 (63%)
0
8
7
22 (65%)
2
5
15
Contralateral breast
1 (4%)
1 (3%)
Secondary non-breast
malignancy
1 (4%)
0
Deaths without failure
1 (4%)
2 (6%)
Site of first failure (after ILRR)
CALOR trial (contd…)
• Efficacy results:
• Multivariate analysis showed treatment
(chemo/ no chemo) to have significant impact
on both DFS and OS
Chemotherapy
No
chemotherapy
HR (95% CI)
P-value
5-yr DFS
ER-positive
ER-negative
69%
70%
67%
57%
69%
35%
0.59 (0.35-0.99)
0.94 (0.47-1.89)
0.32 (0.14-0.73)
.046
.87
.007
5-yr OS
ER-positive
ER-negative
88%
94%
79%
76%
80%
69%
0.41 (0.19-0.89)
0.40 (0.12-1.28)
0.43 (0.15-1.24)
.02
.12
.12
Survival
Considerations for the future
• These need further validation in large cohorts:
Disseminated tumor cells (DTC) •Prognostic in EBC
on BMA assessment
•Marker of recurrence
Circulating tumor cells (CTC)
Poor survival after NACT or
primary breast cancer surgery
cf-DNA (cell free-DNA)
Plasma miRNA
Markers of relapse in EBC
Debate about anthracyclines in HER2 +
Does HER2 over-expression confer a unique and/or inherent
sensitivity to anthracyclines?
• The Topoisomerase IIα Protein 1s a major target of the
anthracyclines
• Current data indicate that it is the TOP2A gene
amplification and not HER2 that is responsible for improved
anthracycline sensitivity
• TOP2A amplification occurs ONLY in 35% of the 25% of
breast cancer patients with HER2 amplification
“only 8% of breast cancer patients”
• Moreover, for HER2-positive breast cancers, trastuzumab
appears to replace the gained efficacy of anthracyclines in
the one third of patients with co-amplification of HER2 and
TOP2A
Predicting anthracycline benefit: TOP2A and CEP17
• Meta-analysis of adjuvant trials that compared
anthracycline-based regimen with CMF –
HER2 amplification and combined TOP2A
amplification or deletion may have some value
in the prediction of response to anthracyclinebased CT, findings do not support the use of
anthracyclines only in patients with HER2amplified or TOP2A aberrated tumors.
questions
• Concept of adjuvant CT in ca breast?
• Which subtype of pt as per ebctcg do not
require CT?
• Subgroup analysis of dose dense CT??
Thank you