Introduction: Neoadjuvant chemotherapy for breast cancer over the last several years is being utilized with increasing frequency.
Neoadjuvant therapy can potentially downstage advanced regional disease, increasing the likelihood of negative surgical margins. This
study analyzes the utilization and outcomes of neoadjuvant chemotherapy for breast cancer at a single institution.
Methods: A retrospective chart review was performed at the Jacqueline M Wilentz Breast Center in Long Branch, New Jersey. All
patients from 2010 to present that underwent neoadjuvant chemotherapy for breast cancer were analyzed. The initial biopsy pathology,
initial staging workup, response to therapy, operation, surgical pathology reports were studied. Chi square analysis was then used to
identify factors more likely to yield a pathologic complete response. Finally, outcomes in patients that did and did not have a pathologic
complete response were examined.
Results: The most common indications for neoadjuvant therapy for advanced regional disease and Her2 positive status. The tumor
was successfully downstaged in 29 of 46 patients (63.0%), with 13 (28.3%) achieving pathologic complete response. The major predictors
of pathologic complete response were chemotherapy regimen and Her2 status, as 12 of 21 patients (57.1%) patients with amplified Her2
and 8 of 12 (66.7%) patients receiving TCHP therapy achieving pCR. Predictive factors of residual disease included triple negative status
and treatment with ACT chemotherapy. Pathologic complete response was predictive of favorable prognosis, as no patient that achieved
a pCR had recurrence, local or distant, within the time frame of this study. Factors predictive of recurrence included residual nodal disease
or residual tumor T3 or greater.
Conclusion: In our retrospective study, neoadjuvant chemotherapy successfully downstages patients in the majority of patients.
The patients that were able to derive the most benefit from neoadjuvant therapy were those with Her2 amplified tumors, and those that
underwent therapy with TCHP. Achievement of pCR incurred a favorable prognosis.
Keywords: Neoadjuvant Chemotherapy; Breast Cancer
Neoadjuvant chemotherapy (NAC) is becoming increasingly
utilized in the treatment of invasive breast cancer. This therapy
has classically been utilized in advanced local disease, and
more recently has been used to increase the likelihood of breast
conservation and negative nodal disease [2,3]. Even more recent
is the use of NAC in the treatment of early stage breast cancer in
an effort to treat the systemic aspects of disease prior to surgery
. One of the potential positive outcomes from NAC is attaining
a pathologic complete response (pCR), defined as no remaining
tumor on pathologic assessment. Studies have suggested that
obtaining a pCR after NAC portends a favorable prognosis, with improved disease free survival rates [5,6]. In this study, a
retrospective review of patients undergoing NAC at a community
institution was analyzed. The aim of this study was to identify
trends in the utilization of NAC in a community setting as well as
factors that may contribute to achieving a pCR. The response of
the primary tumor and the outcomes of patients receiving NAC
was also examined.
After obtaining appropriate Institutional Review Board
approval, ICD-10 and CPT codes were used to identify all
patients that had received NAC at Jacqueline M. Wilentz Breast
Center since 2010. These charts were then examined for patient
demographic data, initial staging workup, chemotherapy
regimen, post-neoadjuvant staging, surgery performed,
pathology reports, and follow up. With this information, rates of
tumor and axillary response were examined along with patient
outcomes, with attention paid to those with pCR. Chi square
analysis and Fisher exact test was then utilized to determine if
certain tumor characteristics or certain chemotherapy regimens
were more likely to predict a pCR. Outcomes were then analyzed
to determine if pCR, among other factors, was predictive of
improved disease free survival.
Forty six patients were identified that met study criteria.
The average age of patients receiving chemotherapy was 54.4 years, and all patients were female. 42.1% of patients had a
family history of breast cancer, and 27.7% of patients underwent
genetic testing. No patients tested positive for BRCA. 42.6% of
patients had a history of smoking. Demographical data is outlined
in Table 1.
Initial average primary tumor size was 4.9 centimeters.
According to the TNM staging classification, 8 (17.4%) patients
had T1 tumors, 14 (30.4%) patients had T2 tumors, 13 (28.2%)
patients had T3 tumors, and 11 (23.9%) patients had T4 tumors.
Of those with T4 tumors, 2 had inflammatory breast cancer. 29
(63.0%) patients had nodal disease at time of diagnosis. 45 of
46 patients had invasive ductal cancer, with the one remaining
having invasive lobular carcinoma. 27 (58.7%) patients were
hormone positive, 22 (47.8%) patients had amplified Her2, and
9 (19.6%) patients were triple negative. Average Ki67 was 49%,
ranging from 10-90%. Histological data is outlined in Table 2.
Chemotherapeutic regimens are outlined in Table 3. The
majority of patients were treated either with ACT (Adriamycin,
Cyclophosphamide, Taxol) or TCH (Taxotere, Carboplatin,
Herceptin). In more recent years of the study, pertuzumab was
added to the TCH regimen (TCHP). There were 24 (52.2%)
patients that underwent treatment with ACT, and 4 (8.7%)
patients had Herceptin added to ACT for Her2 positivity. Five
(10.9%) patients underwent treatment with TCH, and in more
recent years 13 (28.2%) patients underwent treatment with TCHP.
After completion of NAC, patients underwent definitive
surgery. Nine (19.6%) patients underwent breast conserving surgery with lumpectomy and sentinel lymph node biopsy, 4
(8.7%) patients underwent a lumpectomy with axillary lymph
node dissection, 18 (39.1%) patients underwent mastectomy with
sentinel lymph node biopsy, and 15 (32.6%) patients underwent
modified radical mastectomy. Surgical data is outlined in Table 4.
On pathologic analysis, 34 (73.9%) patients demonstrated
regression of the primary tumor. Of the 29 patients that initially
had node positive disease, 13 (44.8%) patients remained node
positive, leaving 16 (55.2%) patients node negative. 2 (4.3%)
patients demonstrated progression of disease, with pathologic
analysis revealing nodal disease not present on initial assessment.
Pathologic complete response was achieved in 13 (28.3%)
patients. Of these 13 patients, 8 were treated with TCHP, 2 with
ACTH, 1 with ACT, and 2 with TCH.
Table 5 outlines factors predictive of pathologic complete
response. Initial tumor characteristics, treatment regimens and
extent of surgery was evaluated using chi square analysis. Her2
positive disease and treatment with TCHP were found to be
factors predictive of pCR. Triple negative disease and treatment
with ACT were found to be predictive of residual disease.
The average follow up period of the study was 39.5 months.
32 (69.6%) patients are currently disease free, including all
13 patients that achieved a pathologic complete response. 14
patients (30.4%) experienced a recurrence, 10 are deceased and
4 are alive with disease. Average disease free survival in patients
that had a recurrence was 24 months, and 13 of 14 patients had a
recurrence within 3 years.
Table 6 outlines factors predictive of tumor recurrence.
Initial tumor characteristics, extent of surgery and pathologic
characteristics were examined using chi square analysis. Factors
predictive of tumor recurrence included bulky residual tumor
(T3 or greater) and residual nodal disease. pCR was found to be
protective against tumor recurrence.
In this study, patients receiving NAC were analyzed over
the past seven years at a single institution. NAC has been demonstrated to be equivalent to adjuvant therapy in terms
of disease free and overall survival [7,8]. One of the tenets
of neoadjuvant therapy is to give patients the opportunity to
undergo breast conserving therapy who would have otherwise
required a mastectomy. Previous studies have demonstrated
that those patients that undergo breast conserving therapy have
equivalent outcomes to those patients that undergo mastectomy
when controlled for stage [9,10]. This appears to hold true for
patients that become candidates for breast conserving therapy
after NAC who would have otherwise needed a mastectomy.
Select patients that undergo breast conserving surgery after NAC
have local disease recurrence rates similar to those that undergo
mastectomy [11,12]. A study out of M.D Anderson identified
predictors of local-regional recurrence and ipsilateral breast
tumor recurrence including advanced nodal involvement at
diagnosis, residual tumor >2 cm, residual multifocal disease and
lymphovascular invasion .
The data from the present study reinforce the information
from these studies. There was no significant difference in localregional
recurrence in patients that underwent breast conserving
surgery when compared to patients that underwent mastectomy.
All recurrences in this study were noted to be distant, with
nearly all recurrences diagnosed within three years of surgery.
Predictors of recurrence in this study included residual nodal
disease and large residual tumor.
When determining appropriate chemotherapy regimens
for patients, selection typically depends on extent of disease at
diagnosis, the histological characteristics of the tumor, and the
patient’s ability to tolerate therapy. At the author’s institution,
patients with non-Her2 amplified disease received ACT therapy
prior to surgery. Patients with Her2 amplification received
TCH. In later portions of the study, patients with Her2 amplified
disease received pre-operative pertuzumab in addition to
the TCH regimen. Studies have demonstrated that treatment
with anthracycline based chemotherapy with docetaxel in the
neoadjuvant setting improves pCR rates and decreases local
recurrence [8,14]. This study demonstrated significant response
to the ACT regimen in terms of regression of the primary
tumor. As a result, several patients were able to undergo breast
conserving surgery. However, only one patient was able to
achieve pathologic complete response, and eleven of the fourteen
patients that recurred were treated initially with ACT. Patients
treated with ACT in this study were more likely to have larger
tumors and nodal disease at time of diagnosis when compared to
patients treated with other regimens.
When treating patients with Her2 positive disease, previous
studies have demonstrated benefit to using trastuzumab.
In the NOAH trial, patients with Her2 positive locally
advanced or inflammatory breast cancer were randomized
to either add trastuzumab in the neoadjuvant and adjuvant
setting or no additional therapy added to their standard
neoadjuvant chemotherapy regimen of doxorubicin, paclitaxel,
cyclophosphamide, methotrexate, and fluorouracil. Addition
of trastuzumab demonstrated improved event-free survival
compared to the control group, without significant cardiotoxicity .
More recently, the addition of pertuzumab to the above
regimen was studied to determine if there was added benefit
in the neoadjuvant setting. As pertuzumab and trastuzumab
both carry risk of cardiotoxicity, the TRYPHAENA study aimed
to determine if pertuzumab could safely be added to a regimen
consisting of trastuzumab. The results of this study demonstrated
the safety of this combination . Pertuzumab has previously
been demonstrated to show benefit in patient with metastatic
Her2 positive breast cancer, as evidenced by the results of the
CLEOPATRA trial. In this trial, patients with first line metastatic
Her2 positive breast cancer were randomized to receive either
pertuzumab, trastuzumab and docetaxel or placebo, trastuzumab
and docetaxel. Over a median follow up of 30 months, the
addition of pertuzumab demonstrated significant improvement
in progression free and overall survival without undue toxicity .
With the results of the CLEOPATRA study, a more recent study
examining pertuzumab with trastuzumab in the neoadjuvant
setting was examined in the Neosphere trial. On initial phase II
analysis, patients were randomized to four separate groups to
receive trastuzumab with docetaxel, pertuzumab with docetaxel,
trastuzumab and pertuzumab with docetaxel, or trastuzumab
and pertuzumab without docetaxel. Patients receiving all three
therapies demonstrated significantly improved pathologic
complete response rates when compared to other groups (45.8%),
and adverse events between all groups were similar . In the
five year follow up analysis of this study, progression free and
disease free survival was analyzed. After undergoing one of the
four above neoadjuvant regimens and surgery, patients received
3 cycles of fluorouracil, epirubicin and cyclophosphamide and an
additional 17 cycles of trastuzumab to complete a year’s worth
of treatment. Results of this analysis suggested that neoadjuvant
pertuzumab in addition to trastuzumab and docetaxel is
beneficial, and that a pCR could be a long term indicator for Her2
positive cancer .
The findings of the present study support the above studies.
In this study, the majority of patients that were able to achieve
pCR were Her2 positive and treated with TCHP. There were
no reported adverse cardiac events related to this regimen.
Moreover, eight of twelve patients treated with TCHP were able
to achieve pCR. It is important to note that patients receiving
neoadjuvant TCHP were more likely to have early breast cancer
with smaller tumors than those patients in earlier portions
of the study. No patients treated with this regimen have had a
recurrence. These data further support the use of TCHP in the
Obtaining pathologic complete response is an important
predictor of outcome in patients undergoing neoadjuvant
therapy. Controversy exists as to what true pCR entails. When
examining existing studies in which pCR is examined, three
commonly used definitions exist. ypT0 ypN0, meaning no
invasive or in situ disease in the breast or axilla, ypT0 ypN0 with
no invasive disease identified (meaning in situ disease only can
still classify as complete response), or ypT0, meaning no invasive
or in situ disease in the breast without specification of disease in
the axilla. The Collaborative Trials in Neoadjuvant Breast Cancer
working group performed an analysis of 12 neoadjuvant trials,
and concluded that those patients that achieved the former two
definitions of pCR had a stronger association with improved
event free and overall survival when compared with the latter
In the present study, pCR was defined as no residual invasive
or in situ cancer on pathologic analysis (ypT0N0). Previous
studies have demonstrated that pCR is associated with a good
prognosis, especially in patients with aggressive subtypes [20-
22, 24]. The results from this study further support pCR as an
indicator of favorable prognosis. All patients that were able to
achieve pathologic complete response are currently disease
free, and the fourteen patients that suffered a cancer recurrence
were not disease free at time of surgery. This suggests that
susceptibility of a breast cancer to chemotherapy portends a
Some subtypes of breast cancer are more responsive to
chemotherapy, and a pCR does not carry the same prognostic
information across all subtypes. Patients with indolent and
hormone positive breast cancers are generally not as sensitive
to chemotherapy as more aggressive subtypes . Additionally,
patients that do not achieve a pCR in the more aggressive subtypes
have a worse prognosis when compared to patients that do,
which does not hold true in patients with more indolent, hormone
positive cancers . The findings of this study support previous
literature, in that patients who underwent chemotherapy for
Her2 amplified disease and triple negative disease appeared to
have higher incidence of pCR. Additionally, this study reaffirms
the favorable prognosis for patients with these subtypes who
achieve pCR, as all patients who achieved pCR in this study are
currently disease free.
After surgery, the question remains what to do next. In the
aforementioned Neosphere study, patients received additional
chemotherapy after completing NAC, and completed trastuzumab
for a year. Patients with Her2 amplified disease in our study also
received adjuvant trastuzumab for one year following surgery.
In Her2-negative patients a recent study examined the use of
adjuvant Capecitabine following neoadjuvant anthracycline or
taxane based chemotherapy for patients with residual carcinoma.
Additional therapy following surgery with Capecitabine was found
to be beneficial, especially in triple negative patients, improving
disease free and overall survival . This study addresses the
question of what to do with our patients with residual disease.
Information from the present study and previous studies
demonstrate poor prognosis for those patients with residual
disease, and the above study aims to address this issue. Further
studies are needed to elucidate optimal management of patients
with residual disease after neoadjuvant therapy.
This study highlights several of the benefits of NAC in patients
with breast cancer. This treatment offers an in vivo assessment
of chemotherapeutic response prior to surgery, providing
important prognostic information. This approach can also be
used in early stage breast cancer to eliminate occult metastatic
disease. Patients that seem to derive most benefit from NAC are
those with more aggressive subtypes, including triple negative
and Her2 amplified patients. This study and previous studies
support the current interest in tailoring therapies to achieve pCR
in aggressive breast cancer subtypes.
In this study, patients undergoing NAC for breast cancer
were typically treated based on extent of disease and tumor
characteristics. NAC successfully decreased tumor size, leading
to the ability to perform breast conserving surgery in some
cases where it may not have otherwise been feasible. Achieving
pathologic complete response was indicative of favorable
prognosis, as all patients that were able to achieve pCR are
currently disease free. Limitations to the study include small
sample size and limited follow up with patients that have more
recently undergone treatment. Further studies are needed to
identify optimal treatment of patients with residual disease after