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THE NATIONAL MEDICAL JOURNAL OF INDIA
VOL. 25, NO. 3, 2012
Original Articles
Pathological complete response in locally advanced breast
cancer: Determinants and predictive significance
V. PARMAR, R. HAWALDAR, N.S. NAIR, T. SHET, S. DESAI, R.A. BADWE
ABSTRACT
Background. Neoadjuvant chemotherapy is now the
standard approach for most large breast cancers including
locally advanced cancers of the breast. The majority of patients
respond satisfactorily to chemotherapy with effective downsizing
of tumours to consider breast conservation surgery. Pathological
complete response (pathCR) is known to be a strong predictor
of good outcome; however, many factors are known to
influence the extent of response to chemotherapy. It has been
observed that smaller the tumour, better is the response
achieved in contrast to larger and locally advanced tumours
where only one-third may respond well enough to merit breast
conservation. Various other clinical, biological and molecular
factors are also being evaluated as effective predictors of
chemosensitivity. Most of these are either not easily available
for all patients in developing countries or are overtly expensive
and not applicable for all patients.
Methods. We evaluated the clinical and pathological
predictors of response to chemotherapy in 1402 women with
locally advanced breast cancer.
Results. There was a higher rate of pathCR in smaller
tumours, younger women and ER-negative as well as triple
negative tumours. The presence of ductal carcinoma in situ
(DCIS) and lymphatic and vascular invasion (LVI) were associated
with lower pathCR.
Conclusion. In the absence of ready availability of expensive
molecular and genomic assays, clinical parameters and standard
histopathological variables can also be useful indicators of
response to neoadjuvant chemotherapy. Additionally, they
can help identify those who could be eventually conserved or
have a better outcome.
Natl Med J India 2012;25:132–6
Tata Memorial Hospital, Ernest Borges Road, Parel, Mumbai 400012,
Maharashtra, India
V. PARMAR, N.S. NAIR, R.A. BADWE Breast Services, Surgical
Oncology
R. HAWALDAR Clinical Research Secretariat
T. SHET, S. DESAI Department of Pathology
Correspondence to V. PARMAR; [email protected]
© The National Medical Journal of India 2012
INTRODUCTION
Neoadjuvant chemotherapy (NACT) is currently offered to most
women with large operable breast cancers desiring breast
conservation therapy (BCT) and nearly all women with locally
advanced breast cancer (LABC) would receive induction
chemotherapy before surgery.1 About 75%–80% of women with
LABC respond to chemotherapy and 28%–30% of women with
LABC have successful BCT.2–4 In spite of a large number of
clinical responders, pathological complete response (pathCR) is
achieved in only a small proportion after NACT (4%–29% of
women with operable breast cancer).5 The post-chemotherapy
nodal status is a known prognostic factor of overall outcome
though NACT itself has not been shown to improve overall
survival.5,6
There have been a number of novel advances in the prediction
of chemoresponsiveness. However, most of these are not available
in the developing world. Also, tumours seen in the developing
world are biologically more aggressive and occur in a relatively
younger population. Therefore, we evaluated the clinical
determinants of response to NACT in 1402 women with LABC
presenting at the Breast Unit at Tata Memorial Hospital, Mumbai
to determine the factors related to pathCR.
METHODS
Data of 1402 women with LABC who received NACT between
1998 and 2006 were assessed for clinical and pathological response.
Treatment protocol
After ruling out any distant metastasis, all women with LABC
received NACT. In all patients, 3–4 cycles of chemotherapy were
administered followed by the first evaluation for response. In the
early part of our study, some patients completed all 6 cycles of
chemotherapy if the response was considered excellent at the first
evaluation. Most women received anthracycline-based chemotherapy (epirubicin [E] 90 mg/m2 or doxorubicin [A] 50 mg/m2
and cyclophosphamide [C] 500 mg/m2 and 5-fluorouracil [F] 500
mg/m2) and a small number received taxanes [T] (docetaxel 100
mg/m2 or paclitaxel 125 mg/m2) along with anthracyclines in the
form of TAC, ET or AT chemotherapy.
Clinical response was evaluated at the primary site alone
(breast), and pathological response was assessed at both the
primary site and the axilla. The clinical response of the primary
tumour was recorded using the WHO criteria: complete response
PARMAR et al. : PREDICTORS OF PATHOLOGICAL COMPLETE RESPONSE IN LABC
(CR) where there was no residual tumour palpable at the primary
site; partial response (PR) where there was >50% reduction in the
primary tumour; static disease (SD) if there was <50% reduction
in the size of the primary tumour; and progressive disease (PD)
where there was an actual increase in primary tumour size after
chemotherapy. Post-chemotherapy, the patients were assessed
clinically and by mammography for feasibility of BCT or modified
radical mastectomy. PathCR was the standard reference point for
CR and was defined as no residual invasive tumour in the breast
and negative axillary lymph nodes after chemotherapy.
Oestrogen receptor (ER), progesterone receptor (PgR) and cerbB2 status was assessed on the core biopsy specimen by the
avidin–biotin complex immunohistochemical technique. A cutoff value of >5% positively stained nuclei in 10 high power fields
was used to define ER and PgR positivity. c-erbB2 scores of 0, 1
and 2 were considered negative, and a score of 3 was considered
positive. We did not have fluorescent in situ hybridization (FISH)
information available on the majority of c-erbB2-positive patients.
Triple negative subtype was defined as ER, PgR and c-erbB2negative.
If feasible, BCT was done after NACT. If the patient was
unsuitable or unwilling for BCT, a modified radical mastectomy
was done. Thirty patients also underwent partial reconstruction
with latissimus dorsi flap for BCT with volume replacement. In
patients where BCT was not feasible, whole breast reconstruction
with free flaps were offered at the time of primary surgery
(mastectomy) to some patients (n=14).
All patients received postoperative radiotherapy (45–50 Gy in
25 fractions) to the whole breast/chest wall over 5 weeks followed
by a tumour bed boost after BCT (10–15 Gy in 6 fractions). All
patients also received supraclavicular fossa irradiation (15 Gy).
Assessing prediction of response
The clinical, epidemiological and treatment factors evaluated
included age at presentation, tumour size, number of cycles of
chemotherapy; involvement of skin (T4 v. rest), clinical status of
axillary lymph nodes (N0–1 or N2), supraclavicular lymph node
(N3 or rest), hormone responsiveness (ER and/or PgR-positive v.
both negative), triple negative tumours (ER, PgR and c-erbB2negative) v. others, menopausal status, lymphatic and vascular
invasion (LVI), tumour grade and extracellular invasiveness,
excess intraductal component (EIC).
Statistical analysis
Univariate and multivariate analysis was done to ascertain
determinants of response to chemotherapy. The factors analysed
were age (<35 years, 36–49 years, 50–65 years and >65 years),
clinical tumour size at presentation (<5 cm or >5 cm), menopausal
status (pre- and perimenopausal, postmenopausal), presence of
EIC, LVI, type of chemotherapy administered (anthracycline v.
taxanes v. CMF), number of chemotherapy cycles (<3, 4 or >4
cycles), c-erbB2 status and hormone receptor status. Clinical
responders (CR and PR) and non-responders (SD and PD), and
those with pathCR v. no pathCR were compared using logistic
regression analysis.
RESULTS
Of the 1402 women with LABC, the majority were <50 years of
age and had tumours >5 cm in size. Most tumours were infiltrating
duct carcinoma, 86.4% were grade III and 41.6% were hormone
responsive. c-erbB2 was estimated in 448 patients and was
positive in 19.9% (Table I). Most patients (93.5%) received
133
anthracycline-based chemotherapy (doxorubicin or epirubicin);
CMF was given to 21 (1.5%) patients and 70 (5%) received
taxanes. A clinical response (CR or PR) was obtained in 1111
patients (79.2%), the remaining had SD or PD (291 patients,
20.8%) and were characterized as non-responders. No residual
disease (pathCR) was present in the breast in 207 patients (14.8%)
whereas pathCR in both breast and axillary lymph nodes was
present in 117 patients (8.3%; Table II). Pathological RD at any
site was present in 1285 patients. Post-chemotherapy lymph
nodes negative for metastases were seen in 459 patients (32.7%).
Predictors of clinical breast tumour response (CR+PR v. SD+PD)
Clinical tumour response was the main determinant for type of
surgery offered (BCT or modified radical mastectomy). Age,
menopausal status, EIC and hormone receptor expression failed
to predict the true clinical response to chemotherapy. On univariate
analysis, extent of responders (CR+PR) of the primary invasive
tumour to chemotherapy was lower in LVI-positive (71.6% v.
82%, p<0.001), better in smaller tumours (82.7% in <5 cm v.
77.6% in >5 cm, p=0.029), better with taxanes than anthracyclines
or CMF (90% v. 78.9% v. 61.9%, p=0.012) and higher with >4
cycles than with <3 cycles of chemotherapy (82.5% v. 73.0%,
TABLE I. Clinical features at presentation, treatment summary and
histological features
Feature
Group
Age
Clinical tumour size
Menopausal status
Skin involvement
Lymph nodes
Matted axillary
Supraclavicular
Chemotherapy
Number of cycles
Type
Surgery
Histological feature
Tumour type
Tumour grade
Excess intraductal
component
Lymphatic and
vascular invasion
Axillary nodal status
Hormone receptors
(ER and PgR)
c-erbB2 (n=448)
ER, PgR and c-erbB2
(n=448)
n
%
<50 years
>5 cm
Pre- and peri-menopausal
T4
851
949
730
768
60.7
67.7
52.0
54.8
Clinically positive (n=1077)
N3
507
196
47.0
14.0
Up to 4
CMF
Anthracyclines
Taxane plus anthracyclines
1032
21
1311
70
82.6
1.5
93.5
5
Breast conservation
426
30.3
Intraductal carcinoma
Grade III
Positive
1377
1158
131
98
86.4
11.4
Positive
337
28.6
Positive
Positive
943
555
67.3
41.6
Positive
Triple negative
89
198
19.9
44.2
CMF cyclophosphamide, methotrexate, 5-fluorouracil
PgR progesterone receptor
ER oestrogen receptor
TABLE II. Pathological response after neoadjuvant chemotherapy
(n=1402)
Response
Complete
Residual disease
Breast alone (primary)
Breast and axilla
n
%
n
%
207
1195
14.8
85.2
117
1285
8.3
91.7
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VOL. 25, NO. 3, 2012
THE NATIONAL MEDICAL JOURNAL OF INDIA
p<0.001). On multivariate analysis, the variables predicting a
better clinical response were absence of LVI, taxane administration
and 4 or more cycles of chemotherapy (Table III).
analysis, younger women (<35 years of age), smaller tumours
(<5 cm), EIC-negative, LVI-negative, hormone receptor negative,
triple negative and >4 cycles of chemotherapy had a higher
percentage of pathCR (Table IV).
On multivariate analysis, there was a better pathCR in younger
women (OR 0.57, 95% CI 0.40–0.78, p=0.001) with a 43%
relatively poorer response with unit increase in age. PathCR was
Predictors of pathCR
PathCR in both breast and axillary lymph nodes was considered
the gold standard as it affects the overall outcome. On univariate
TABLE III. Predictors of clinical response of the breast tumour
Variable
Age (years)
Clinical tumour size (cm)
Menopausal status
Excess intraductal component
Lymphatic and vascular invasion
Chemotherapy
Type
Number of cycles
ER/PgR
ER/PgR/c-erbB2 (n=579)
Subgroup
n
Complete and
partial response
n
%
<35
36–49
>50
<5
>5
Pre- and periPostPositive
Negative
Positive
Negative
197
654
551
452
949
730
672
140
1154
363
957
149
536
426
374
736
580
531
114
911
260
785
75.6
82.0
77.3
82.7
77.6
79.5
79.0
81.4
78.9
71.6
82.0
CMF
CAF/CEF
Taxanes
<3
>4
Any positive
Both negative
Triple-negative
Others (including
c-erbB2 positive)
21
1311
70
486
916
555
778
268
311
13
1035
63
355
756
446
609
214
250
61.9
78.9
90.0
73.0
82.5
80.4
78.3
79.9
80.4
CMF cyclophosphamide, methotrexate, 5-fluorouracil
ER oestrogen receptor
PgR progesterone receptor
CAF cyclophosphamide, adriamycin, 5-fluorouracil
Univariate
p value
Odds ratio
(95% CI)
p value
<0.053
1.12 (0.86–1.46)
NS
<0.029
1.24 (0.91–1.71)
NS
<0.840
0.91(0.61–1.35)
NS
<0.580
1.21 (0.75–1.95)
NS
<0.001
0.58 (0.43–0.79)
0.001
<0.012
0.50 (0.26–0.97)
0.040
<0.001
0.63 (0.47–0.85)
0.002
<0.370
1.11 (0.83–1.45)
NS
<0.917
—
—
CEF cyclophosphamide, epirubicin, 5-fluorouracil
TABLE IV. Factors influencing a complete pathological response (pathCR)
Variables
Age (years)
Clinical tumour size (cm)
Menopausal status
Excess intraductal component
Lymphatic and vascular invasion
Chemotherapy
Type
Number of cycles
ER/PgR
ER/PgR/c-erbB2 (n=579)
Subgroup
n
pathCR
n
%
<35
36–49
>50
<5
>5
Pre- and periPostPositive
Negative
Positive
Negative
197
654
551
452
949
730
672
140
1154
363
957
20
65
32
48
69
68
49
3
96
6
92
10.2
9.9
5.8
10.6
7.3
9.3
7.3
2.1
8.3
1.7
9.6
CMF
CAF/CEF
Taxanes
<3
>4
Any positive
Both negative
Triple negative
Others
21
1311
170
486
916
555
778
268
311
1
110
6
21
96
15
83
29
13
4.8
8.4
8.6
4.3
10.5
2.7
10.7
10.8
4.2
CMF cyclophosphamide, methotrexate, 5-fluorouracil
ER oestrogen receptor
PgR progesterone receptor
CAF cyclophosphamide, adriamycin, 5-fluorouracil
Univariate
p value
Odds ratio
(95% CI)
0.042
0.57 (0.40–0.78)
0.001
0.039
0.54 (0.33–0.88)
0.015
NS
—
p value
—
0.006
15.3 (1.26–22.3)
0.023
<0.001
4.54 (1.93–10.6)
0.001
NS
—
—
<0.001
1.54 (1.09–2.18)
0.013
<0.001
4.92 (2.55–9.52)
<0.001
0.003
—
—
CEF cyclophosphamide, epirubicin, 5-fluorouracil
PARMAR et al. : PREDICTORS OF PATHOLOGICAL COMPLETE RESPONSE IN LABC
better when >4 cycles of NACT were administered (10.5% v.
4.3%, OR 1.54, 95% CI 1.09–2.18, p=0.013); 1.7% women with
LVI-positive disease had a pathCR as against 9.6% of women
with LVI-negative disease (OR 4.54, 95% CI 1.93–10.6, p=0.001;
Table IV).
Patients whose tumours did not express ER and PgR also
showed a better response to NACT than the receptor positive
subgroup (10.7% v. 2.7%, OR 4.92, 95% CI 2.55–9.52, p<0.001),
and so also the triple negative subgroup (n=268) of tumours
10.8% v. 3% in non-triple negative tumours (p<0.0001). For this
analysis, women with tumours that were either ER/PgR positive
with unknown c-erbB2 status were considered as non-triple
negative (n=311). In fact, in all women who eventually had a
pathCR, 60.4% were triple negative.
DISCUSSION
NACT is really an in vivo testing of chemosensitivity of the
tumour (and thus indirectly of prognosis). If the response to
chemotherapy could be predicted at the time of starting therapy,
it could help to utilize resources efficiently, avoid expensive
chemotherapy and lead to appropriate treatment planning .7
Various clinical,8,9–12 biological,13–16 imaging, molecular
factors and gene-expression signatures have been evaluated as
effective predictors of chemosensitivity. The biological factors13
evaluated include hormone receptor expression (ER and PgR),14–16
HER2neu/c-erbB2, 17 Topoisomerase II alpha, 18–23 Ki-67
proliferative index, Bcl-2 (apoptotic index) and other proliferative
and apoptotic indices.24–28 The imaging modalities evaluated
include MRI,29–31 PET scan32,33 and 99mTc-sestamibi scans.34,35
Genomics and proteomics with microarray studies are currently
being evaluated.36–39
The clinical, pathological11 and biological markers40 of
chemosensitivity are the most extensively studied factors (Table
V). Younger women with high-grade tumours that are ER- and
PgR-negative, with low Bcl-2 expressions and high proliferative
index (Ki-67) have been shown to respond better to chemotherapy.
ER-positive and PgR-positive tumours are known to respond
better to hormonal therapy.40 Higher HER2/neu score or epidermal
growth factor receptor (EGF-R) show a weak correlation with
response to chemotherapy, higher sensitivity to monoclonal
antibody therapy, and better response to letrozole therapy.24–26
Mammography has been routinely used post-chemotherapy to
evaluate the extent of tumour response and to decide feasibility of
TABLE V. Factors associated with response to chemotherapy
Increased sensitivity to chemotherapy
• Young age, high-grade tumour, oestrogen receptor negative,
progesterone receptor negative, low Bcl-2 expression and high Ki-67
proliferative index41
• Increased expression of BRCA1 (anthracycline sensitive)41
• Low BRCA2 mRNA42 (favourable response to chemotherapy)
• Microtubule-associated protein tau is a marker of paclitaxel sensitivity43,44
Reduced sensitivity to chemotherapy
• Oestrogen receptor positive, progesterone receptor positive (higher
response to hormonal therapy)41
• Increased expression of Skp2 (doxorubicin resistance)45
• Intratumoral CYP3A4 high expression suggests docetaxel resistance46
• Class I and III beta tubulin isotype mRNA (lowered docetaxel sensitivity)44
Poor correlation with response to chemotherapy
• HER2/neu, epidermal growth factor receptor (predicts relatively higher
response to chemotherapy)24–26
• p5347
135
BCT. Ultrasonography has been shown to correlate with
pathological response in 50%–60% of cases.48 Quantitative MRI
and Proton Spectroscopy (MRS) assess tumour response by per
cent volume reduction with 50%–70% accuracy,31 but are not
used routinely as these have high false-positivity.
In this large subset of women with LABC, with NACT
(anthracycline-based) administered in majority, 79.2% women
showed a clinical tumour response (CR+PR) with pathCR in
8.3% cases. Substituting by or addition of a taxane to neoadjuvant
anthracycline appears to increase the overall clinical response rate
(CR+PR) to 90% compared to 78.9% with anthracyclines, but
does not appear to improve the pathCR (8.6% v. 8.4%, p=NS).
Thus, anthracyclines may also be an appropriate choice for NACT
both in terms of cost and benefit. Taxanes can be offered as a noncross-resistant protocol in the adjuvant setting for inadequate
pathological tumour response without affecting the outcome.
The presentation was observed at a later clinical stage in a
majority of cases with a median clinical tumour size of 7 cm
indicating a later stage of presentation with T4 tumours seen in
more than half the cases. There was an effective downstaging both
at the primary site as well as in the axilla with anthracycline
chemotherapy. Post-chemotherapy axillary downstaging occurred
in 10% women. BCT was offered in nearly one-third of the
patients.
There was a better response in smaller tumours, younger age
and ER-negative tumours as well as in those who were triple
negative with a higher rate of pathCR. Response was also better
with more cycles of chemotherapy (>4 cycles). However, there is
a bias in this observation as patients who were clinically
documented to have an excellent response to chemotherapy in the
first 3–4 cycles went ahead to complete the remaining cycles.
Most of the tumours were higher grade and a better response was
seen in these tumours. Response was mostly incomplete in the
EIC-positive (with residual DCIS) and LVI-positive tumours.
The literature also supports the finding observed in our subgroup
of patients with younger women showing better response11 as also
hormone receptor-negative tumours being more chemosensitive.39
More number of chemotherapy cycles resulting in better pathCR
was clearly as exemplified in the NSABP B27 study wherein, the
arm receiving four cycles of anthracycline chemotherapy followed
by four more cycles of paclitaxel in the neoadjuvant setting
showed a better pathCR rate than those who received four cycles
of anthracyclines followed by surgery and then four cycles of
paclitaxel chemotherapy in the adjuvant setting. In other words,
eight cycles of chemotherapy before surgery were more effective
in achieving a better response than just four cycles of anterior
chemotherapy.12
The triple negative subgroup although did not demonstrate a
clinically superior response to NACT, clearly showed a
significantly higher rate of pathCR (10.8% v. 4.2%, p=0.003)
compared to the non-triple negative subtypes. This has been
observed in other reports as well but whether this translated into
a better survival is not known. The follow-up of these women is
currently ongoing to see the correlation and significance of the
extent of clinical and pathological tumour response to long-term
outcome.
Conclusion
In the absence of molecular and genomic assays, clinical parameters
and histological features can provide useful indicators of response
to NACT. This could help in treatment planning in countries with
limited resources.
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