Ann Surg Oncol (2018) 25:3535–3540
https://doi.org/10.1245/s10434-018-6608-1
ORIGINAL ARTICLE – BREAST ONCOLOGY
Impact of Neoadjuvant Chemotherapy on Breast Cancer Subtype:
Does Subtype Change and, if so, How?
IHC Profile and Neoadjuvant Chemotherapy
Lucy M. De La Cruz, MD1, Michael O. Harhay, PhD2, Paul Zhang, MD, PhD3, and Stacy Ugras, MD1
1
Department of Surgery, Division of Endocrine and Oncologic Surgery, University of Pennsylvania Health System,
Philadelphia, PA; 2Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia,
PA; 3Department of Pathology, Hospital of the University of Pennsylvania, Philadelphia, PA
ABSTRACT
Background. Breast cancer subtype, as determined by the
expression of estrogen receptor (ER) and progesterone
receptor (PR), together defined as hormone receptor (HR)
status, and the HER2/neu receptor (HER2), is important in
predicting prognosis and guiding therapy. Knowledge
regarding how tumors evolve during treatment and whether
subtype is influenced by neoadjuvant chemotherapy (nCT)
is limited. The purpose of this study was to compare the
HR and HER2 status between core needle biopsy and
residual tumor after surgery of breast cancer patients
treated with nCT and to evaluate the impact of status
change on therapeutic management.
Methods. After institutional review board approval, we
performed a retrospective review of all patients with a
diagnosis of breast cancer who received nCT and had their
initial biopsy and post-nCT surgical specimens evaluated
for tumor subtype between January 2009 and December
2014 at our institution. Immunohistochemistry (IHC) of
ER, PR, HER2, and fluorescence in situ hybridization for
HER2 expression, when indicated, was performed using
identical technique and measured by a single pathologist
who specializes in breast pathology. Pre- and post-nCT
Electronic supplementary material The online version of this
article (https://doi.org/10.1245/s10434-018-6608-1) contains
supplementary material, which is available to authorized users.
Ó Society of Surgical Oncology 2018
First Received: 14 February 2018;
Published Online: 6 July 2018
S. Ugras, MD
e-mail: stacy.ugras@gmail.com
subtype was cross-tabulated to assess change. Standard
diagnostic metrics were computed.
Results. Fifty-two patients with 54 cancers were identified
to have their initial biopsy and post-nCT surgical speci-
mens evaluated for tumor subtype in identical fashion.
There was a complete pathologic response after nCT in 23
cancers (42.6%). Residual disease was noted in 31 cancers
(57.4%). Five of these (16.1%) had a change in tumor
subtype, of which four changes were based on IHC. HR
status changed from positive to negative in two cases and
from negative to positive in one case. HER2 status changed
from positive to negative in one case and from negative to
positive in one case. Subtype change led to treatment
change in all five cases, with either the addition or dis-
continuation of adjuvant therapies.
Conclusions. Patients with breast cancer may experience
alterations in their tumor subtype after nCT. At our insti-
tution, this led to a change in adjuvant treatment in 100%
of such patients. This implies that retesting receptor status
of residual tumors after nCT should be routinely performed
to tailor adjuvant therapy after nCT.
Breast cancer treatment strategies rely on the accurate
determination of hormone receptor status and human epi-
dermal growth factor receptor 2 (HER2) status to establish
the use of hormone-directed and HER2-targeted therapies.
This determination is based on immunohistochemistry
(IHC) of the estrogen receptor (ER) and progesterone
receptor (PR), together defined as hormone receptor (HR)
status, IHC of HER2, as well as fluorescence in situ
hybridization (FISH) for HER2 gene amplification, when
indicated. The expression of these receptors defines four
distinct breast cancer subtypes: HR positive/HER2
3536
negative (HR ?/HER2 -); HR positive/HER2 positive
(HR ?/HER2 ?); HR negative/HER2 positive (HR -/
HER2 ?); and HR negative/HER2 negative (HR -/
HER2 -), also known as triple-negative (TN). This
information is used to guide systemic therapy as well as
predict response to treatment and prognosis.
In the current era of breast cancer therapy, neoadjuvant
chemotherapy (nCT) is being used with increased fre-
quency. In locally advanced breast cancer, nCT has been
shown to downstage tumors and increase the rate of breast
conserving surgery without compromising long-term out-
come.1–4 Information regarding how tumors evolve during
treatment and whether subtype is influenced by nCT is
limited, despite the potentially significant impact that this
would have on treatment and prognosis.5–10
The purpose of this study was to compare breast cancer
subtype, as defined by IHC of ER, PR, and HER2, and
FISH for HER2 expression, when indicated, before and
after nCT to assess the effect of treatment on receptor
status and impact on treatment decisions.
PATIENTS AND METHODS
Study Design and Patient Cohort
After institutional review board approval at the
University of Pennsylvania, we performed a retrospective
review of patient data between January 2009 and Decem-
ber 2014. Tumors from patients with histologically
confirmed invasive breast cancer who received nCT were
included if they had both their prechemotherapy biopsy and
postchemotherapy surgical specimens evaluated at the
Hospital of University of Pennsylvania laboratory. Tumors
for which we did not have complete pre- and post-nCT HR
and HER2 status information, tumors for which pre- and
post-nCT specimens were not evaluated at our laboratory,
and tumors from patients who had a pathologic complete
response (pCR) after nCT were excluded (Fig. 1).
Neoadjuvant chemotherapeutic regimens for treated
patients included combination anthracyclines, taxanes, and
alkylating agents. Pathology reports for both pre- and
posttreatment specimens were evaluated and data, includ-
ing tumor size, histologic subtype (ductal, lobular, other),
ER, PR, and HER2 status, were collected for each tumor.
Through review of surgical pathology reports and onco-
logic records, clinical information, including patient age,
cancer stage, and treatment type (systemic therapy and
surgery), was obtained. For all included tumors, the HR
and HER2 IHC and/or HER2 FISH results were available
for both the pretreatment core needle biopsies and post-
nCT surgical specimens.
L. M. De La Cruz et al.
Treatment
Patients received nCT according to the standard proto-
cols of our institution based on guidelines. Patients
received several neoadjuvant regimens (Supplemental
Table S1). In the HER2-positive patients, all received
Herceptin alone as their HER2 targeted therapy. Three
patients in the original cohort received pertuzumab but
were excluded, because they had a pCR. nCT was followed
by lumpectomy or mastectomy with sentinel lymph node
biopsy or axillary node dissection.
Assessing Pathologic Tumor Response to Neoadjuvant
Chemotherapy
Pathologic examination and IHC were reviewed by a
single, dedicated, breast pathologist (PJZ). Histopathologic
features were assessed on slides of formalin-fixed, paraffin-
embedded tissue stained with hematoxylin and eosin.
Lesions were graded according to Nottingham modification
of Bloom-Richardson system. ER, PR, and HER2 status
was determined with commercially available, FDA-ap-
proved, ER/PR PharmDx tests and HercepTest (DAKO/
Agilent, Santa Clara, CA). This was performed in the
Laboratory of Diagnostic Immunohistochemistry at the
Hospital of the University of Pennsylvania at the time of
the initial diagnosis following the FDA-approved manu-
facturer procedure guidelines. Only nuclear reactivity for
ER and PR and membrane reactivity for HER2 were con-
sidered significant, respectively. Cases were considered
positive for ER or PR when the Allred score was 3 or
higher. HER2 was scored as positive when HER2 reactivity
was 3 ? in more than 10% of tumor cells. FISH testing
was performed in patients in whom the IHC of HER2 was
2 ? and in patients with TN breast cancer, per institution
protocol. FISH assay was performed on the same formalin
section in which IHC was performed using the FDA-ap-
proved Vysis PathVysion Her-2 DNA probe kit (Abbott
Laboratories. Abbott Park, IL) following the manufacturer
guidelines. HER2 was considered positive when the Her2/
CEP17 ratio was [ 2.0 or the Her2/cell ratio was [ 6.0.
Based on the result of ER, PR, and HER2 testing, the cases
were classified into the four subgroups; HR ?/HER2 - ,
HR ?/HER2 ? , HR -/HER2 ? , and HR -/HER2 - .
We defined pCR as complete histopathologic absence of
invasive and noninvasive tumor cells in all removed breast
specimens and axillary lymph nodes (ypT0 ypN0).
Statistical Analyses
The sample size (i.e., frequency) and percent of the total
were calculated for selected demographic and clinical
variables at baseline and after neoadjuvant chemotherapy.
IHC Profile and nCT 3537

FIG. 1 Study flow

105 patients received neoadjuvant chemotherapy
therapy

53 patients excluded due to tumors without

complete corresponding pre- and post- HR
and HER2/neu expression profiles; no surgical
pathology available

52 patients included (54 cancers) after initial search

22 patients excluded (23 cancers) with

pathologic complete response on final
pathology

30 patients with residual disease (31 cancers)

included in the study

HER2/neu-Human Epidermal Growth Factor 2; HR: Hormone Receptor

A transition matrix summarizing changes in receptor status Change in Receptor Expression

before and after neoadjuvant chemotherapy was generated
to depict changes in receptor status. Due to the low fre-
quency of changes in receptor status, a multivariable
regression could not be estimated. An individual patient
summary was developed to illustrate tumor characteristics
by treatment regimen.
RESULTS
Fifty-two patients with 54 cancers received nCT and had
pre- and posttreatment IHC profiles performed at our
institution’s laboratory and were included in our study. A
total of 22 patients with 23 cancers (42.6% of cancers) who
received nCT in our study were considered to have a pCR.
These complete responders were excluded from this study
due to the lack of residual tumors. The remaining 30
patients with 31 cancers (57.4% of cancers) with residual
disease in the breast were included in this study (Fig. 1).
One patient with residual disease presented with two can-
cers and had bilateral disease (subject 30) (Supplemental
Table S1). Tumor characteristics are described in Table 1.
The majority of tumors were HR ?/HER2 - (55%) and
presented as stage 2 disease (58%) at diagnosis. The most
common operation was simple mastectomy (77%). Many
(45.5%) patients received Adriamycin/cyclophosphamide/
Taxol (ACT; Supplemental Table S1).
Patients with HR and HER2 status changes after nCT
are listed in Table 2. Tumor subtype changed in five
patients after nCT, 9.62% of the entire study cohort, and
16.7% of those without a pCR. In two cases, HR status
converted from positive to negative. In one case, HR status
changed from negative to positive. In one case, HER2
status changed from positive to negative. In another case,
HER2 status changed from negative to positive, but this
was based on FISH testing in the post-nCT surgical spec-
imen. FISH was not performed on the pre-nCT specimen.
The IHC for HER2 in this case was negative in both the
pre- and post-nCT specimens. There were no cases in
which both HR and HER2 status changed.
The changes in HR and HER2 status led to alterations in
therapy for all five patients. A change in HR status from
positive to negative led to the discontinuation of adjuvant
endocrine therapy in two patients, and a change from
negative to positive led to the addition of endocrine therapy
in one patient after surgery. HER2 status change from
positive to negative led to the discontinuation of Herceptin
in one patient, and a change from negative to positive led to
its addition in one patient (Supplemental Table S2).
DISCUSSION
Currently, there are conflicting theories regarding the
impact of nCT on HR and HER2 status in breast cancer.
Some groups suggest that residual disease after nCT
3538 L. M. De La Cruz et al.

TABLE 1 Tumor characteristics (n = 31) TABLE 1 continued

Pre-neoadjuvant chemotherapy Post-neoadjuvant chemotherapy

Age at diagnosis (years)—mean (SD), median 52 (11.7), 52 (45- 2? 2 (6)

(IQR) 59) 3? 3 (10)
Clinical T stage at presentation FISH—n (%)
1 2 (6) Positive 3 (10)
2 18 (58) Negative 4 (13)
3 5 (16) HR pos/HER2 neg 16 (52)
4 4 (13) HR pos/HER2 pos 4 (13)
Unknown 2 (6) HR neg/HER2 pos 2 (6)
Clinical nodal status at presentation—n (%) HR neg/HER2 neg 9 (29)
Positive 25 (81) SD standard deviation, IHC immunohistochemistry, FISH floures-
Negative 6 (19) cence in situ hibridization, HR hormone receptor, neg negative, pos
Histologic subtype at presentation—n (%) positive
a
Ductal 31 (100) One case with HER2 status pre-nCT identified by FISH and not IHC
Lobular 0
contains the cancer cell population intrinsically resistant to
Others 0
chemotherapy and therefore the HR and HER2 status after
Estrogen receptor status—n (%)
nCT mirrors the micrometastatic component of the disease
Negative 12 (39)
that is ultimately responsible for distant metastases.11
Positive 19 (61)
Intratumoral phenotypic heterogeneity is considered a
Progesterone receptor status—n (%)
defining characteristic of human tumors, and other groups
Negative 14 (45)
suggest that the small tissue samples, typically obtained by
Positive 17 (55)
biopsy, may not be representative of the whole tumor and
HER2/neu (IHC)—n (%)a
that subtype change is due to sampling error.12 Another
0/1? 24 (77)
theory is that given tumor heterogeneity, some populations
2? 1 (3)
of tumor cells die and others repopulate during nCT,
3? 5 (16)
resulting in changes in the level of protein expression and
FISH—n (%) changes in tumor clonal characteristics.13 A study by
Positive 8 (26) Almendro et al.13 demonstrated that intratumoral genetic
Negative 1 (3) diversity was tumor-subtype specific, with lower pretreat-
HR pos/HER2 neg 17 (55) ment genetic diversity being associated with a pCR.
HR pos/HER2 pos 4 (13) While groups have questioned the effect of nCT on
HR neg/HER2 pos 2 (7) measured levels of ER, PR, or HER2, there is no clear
HR neg/HER2 neg 8 (26) consensus in the literature of whether subtype actually
Post-neoadjuvant chemotherapy evolves with chemotherapy and with what frequency. It is
not currently the standard of care to retest post-nCT sur-
Surgery type—n (%)
gical specimens for receptor expression, making it difficult
Lumpectomy 7 (23)
to perform such studies using available databases. A study
Simple mastectomy 24 (77) by Qin et al. evaluated pre- and post-neoadjuvant
Modified radical mastectomy 0 chemotherapy paired-tumor specimens from 103 patients
Estrogen receptor status—n (%) with breast cancer and found no significant change in IHC
Negative 13 (42) staining of ER, PR, and HER2 expression, although they
Positive 18 (58) found the Ki-67 index decreased after neoadjuvant
Progesterone receptor status—n (%) chemotherapy.14 In contrast, Lim et al. evaluated subtype
Negative 17 (55) conversion and found significant changes in subtype after
Positive 14 (45) nCT. Findings included HR ?/HER2 - tumors converting
HER2/neu (IHC)—n (%) to TN in 10.3% of cases and TN tumors gaining HR pos-
0 17 (55) itivity to become HR ?/HER2 - in 34.6% of cases.
1? 9 (29) Clinical outcomes associated with subtype conversion also
were analyzed. Results indicated poorer survival in the
group of HR ?/HER2 - tumors that converted to TN
IHC Profile and nCT
TABLE 2 Tumors with change in receptor status
Post-neoadjuvant chemotherapy
HR pos/HER2 neg
Pre-neoadjuvant HR pos/HER2 neg 15
chemotherapy HR pos/ HER2 pos 1a
HR neg/ HER2 pos 0 1a
HR neg/HER2 neg 0 0
n 16
HR hormone receptor, HER2 human epidermal growth factor 2, neg negative, pos positive
a
Patients with receptor status change
compared with those that remained HR ?/HER2 - .
Patients with tumors that converted from TN to HR ?/
HER2 - had improved survival outcomes. Patients in
whom tumors remained TN had the worst outcome.15
As the use of nCT is increasing in frequency, the impact
of a change in tumor subtype becomes more important to
identify, because it may alter adjuvant endocrine and anti-
HER2 therapy. In our study, we found that breast tumors
did actually undergo subtype conversion after nCT in a
small group of patients. The rate of change in HR status
noted in our study was 10% in patients with residual tumor
present (3 of 30 patients), which is in range with other
reported studies.16,17 In contrast, our study demonstrated a
lower rate of HER2 status change compared with prior
studies; 6.7% in patients with residual tumor present (2 of
30 patients).16,17
In their systematic review, Kroep et al. found 32 studies
comparing HR and HER2 status after nCT with or without
trastuzumab. A change in HR status was reported in 8–33%
of the patients, with approximately half of the studies
noting a change of 2.5–17% in ER status and 5.9–51.7% in
PR status. A change from positive to negative HER2 status
was seen in up to 43% of the patients. These patients
underwent nCT combined with trastuzumab.7 Hirata
et al.17 reported ER, PR, and HER2 status changes in 14.9,
29.1, and 9.5% of their group of patients, respectively. HR
status conversion occurred in 16.0% of their patients.
Whereas in these and our study, a change in ER, PR, and
HER2 status occurred in the minority of cases, these
changes significantly impact the clinical management of
these patients. According to our results, changes in the
tumor subtype after nCT altered adjuvant therapy in 100%
of patients. We expect that addition of endocrine or anti-
HER2 therapy in cases with conversion to positive HR and
HER2 status will improve outcome. On the other hand, we
expect that the discontinuation of potentially unnecessary
endocrine or anti-HER2 therapy may improve patients’
quality of life. Currently, the use of nCT increases rates of
3539
n
HR pos/ HER2 pos HR neg/ HER2 pos HR neg/HER2 neg
1a 0 1a 17
2 1 a
0 4
1 0 2
0 8 8
4 2 9
breast conservation for locally advanced tumors that would
have required mastectomy before chemotherapy. Given our
studies’ findings, another advantage of nCT could be to
improve outcome by allowing clinicians to tailor adjuvant
therapy based on changes in receptor status after nCT.18,19
Despite generating relevant clinical findings, we
acknowledge that this study has some limitations. First, it
was retrospective in nature. Our patient population was
heterogeneous and small in size. Therefore, it was not
possible to control for the type of nCT or adjuvant treat-
ment that the patients received or to exclude selection bias
with regards to type of therapy given. In our cohort, 77% of
cases were treated with mastectomy after nCT, which is
high given nCT should increase breast conservation
rates.18,19 There was some inconsistency in the use of IHC
and FISH for HER2, as noted by the one tumor for which
IHC was not used pre-nCT and the other tumor that was
tested for FISH post-nCT but not pre-nCT. As such, one of
our five tumors with subtype change may have been due to
the fact that HER2 FISH testing was performed after nCT
but was not performed on the pre-nCT specimen. Fur-
thermore, in our institution we do not routinely test for Ki-
67, which some studies suggest may decrease with nCT
and also be used to predict pCR.20
CONCLUSIONS
Our study demonstrates that patients with breast cancer
may experience change in their tumor subtype after nCT.
This implies that HR and HER2 status should be evaluated
not only in the biopsy specimens obtained before the ini-
tiation of nCT but also in specimens obtained during post-
nCT surgery; the pre- and post-nCT biomarker status can
guide adjuvant therapy in these patients. At our institution,
this led to a change in adjuvant treatment in 100% of such
patients. Also, in the era of genetic profiling and HER2-
3540
targeted therapy, long-term outcomes of patients with HR/
HER2 status conversions may differ significantly, and
further studies may shed light on this patient population.
AUTHORS’ CONTRIBUTION SU conception, design, and edit-
ing/revision of manuscript. LC and SU performed data acquisition.
LC drafted the initial manuscript. MH performed the statistical
analyses. PJZ reviewed slides. LC, MH, SU, and PJZ assisted in
critical revision of the manuscript. All authors reviewed, revised, and
approved the final manuscript as submitted and agree to be
accountable for all aspects of the work.
DISCLOSURES The authors have no financial relationships or
conflicts of interest relevant to this article to disclose.
REFERENCES
1. Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher
ER. Effect of preoperative chemotherapy on the outcome of
women with operable breast cancer. J Clin Oncol.
1998;16(8):2672–85.
2. Bartlett JM, Brookes CL, Robson T, van de Velde CJ, Billingham
LJ, Campbell FM. Estrogen receptor and progesterone receptor as
predictive biomarkers of response to endocrine therapy: a
prospectively powered pathology study in the Tamoxifen and
Exemestane Adjuvant Multinational trial. J Clin Oncol.
2011;29(12):1531–8.
3. van der Hage JA, van de Velde CJ, Julien JP, Tubiana-Hulin M,
Vandervelden C, Duchateau L. Preoperative chemotherapy in
primary operable breast cancer: results from the European
Organization for Research and Treatment of Cancer trial 10902. J
Clin Oncol. 2001;19(22):4224–37.
4. Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvant versus adjuvant
systemic treatment in breast cancer: a meta-analysis. J Natl
Cancer Inst. 2005;97(3):188–94.
5. Chen S, Chen CM, Yu KD, Zhou RJ, Shao ZM. Prognostic value
of a positive-to-negative change in hormone receptor status after
neoadjuvant chemotherapy in patients with hormone receptor-
positive breast cancer. Ann Surg Oncol. 2012;19(9):3002–11.
6. Lee SH, Chung MA, Quddus MR, Steinhoff MM, Cady B. The
effect of neoadjuvant chemotherapy on estrogen and progesterone
receptor expression and hormone receptor status in breast cancer.
Am J Surg. 2003;186:348–50.
7. van de Ven S, Smit VT, Dekker TJ, Nortier JW, Kroep JR.
Discordances in ER, PR, and HER2 receptors after neoadjuvant
chemotherapy in breast cancer. Cancer Treat Rev.
2011;37:422–30.
8. Zhang N, Moran MS, Huo Q, Haffty BG, Yang Q. The hormonal
receptor status in breast cancer can be altered by neoadjuvant
chemotherapy: a meta-analysis. Cancer Invest. 2011;29:594–8.
9. Burcombe RJ, Makris A, Richman PI, Daley FM, Noble S, Pittam
M. Evaluation of ER, PgR, HER-2 and Ki-67 as predictors of
L. M. De La Cruz et al.
response to neoadjuvant anthracycline chemotherapy for operable
breast cancer. Br J Cancer. 2005;92:147–55.
10. Shet T, Agrawal A, Chinoy R, Havaldar R, Parmar V, Badwe R.
Changes in the tumor grade and biological markers in locally
advanced breast cancer after chemotherapy—implications for a
pathologist. Breast J. 2007;13:457–64.
11. Balko JM, Giltnane JM, Wang K, Schwarz LJ, Young CD, Cook
RS. Molecular profiling of the residual disease of triple-negative
breast cancers after neoadjuvant chemotherapy identifies action-
able therapeutic targets. Cancer Discov. 2014;4(2):232–45. h
ttps://doi.org/10.1158/2159-8290.cd-13-0286. Epub 2013 Dec 19.
12. Gerlinger M, Rowan AJ, Horswell S, Math M, Larkin J, Endes-
felder D, Gronroos E, Martinez P. Intratumor heterogeneity and
branched evolution revealed by multiregion sequencing. N Engl J
Med. 2012;366(10):883–92.
13. Almendro V, Cheng YK, Randles A, Itzkovitz S, Marusyk A,
Ametller E. Inference of tumor evolution during chemotherapy
by computational modeling and in situ analysis of genetic and
phenotypic cellular diversity. Cell Rep. 2014;6(3):514–27. http
s://doi.org/10.1016/j.celrep.2013.12.041. Epub 2014 Jan 23.
14. Qin Q, Gao F, Jiang W, Tan Q, Mo Q, Wei C. Effect of
neoadjuvant chemotherapy on expressions of estrogen receptor,
progesterone receptor, human epidermal growth factor receptor 2,
and Ki-67 in breast cancer. Chin Med J (Engl).
2014;127(18):3272–7.
15. Lim SK, Lee MH, Park IH, You JY, Nam BH, Kim BN. Impact
of molecular subtype conversion of breast cancers after neoad-
juvant chemotherapy on clinical outcome. Cancer Res Treat.
2016;48(1):133–41. https://doi.org/10.4143/crt.2014.262. Epub
2015 Apr 7.
16. Tacca O, Penault-Llorca F, Abrial C, Mouret-Reynier MA,
Raoelfils I, Durando X, et al. Changes in and prognostic value of
hormone receptor status in a series of operable breast cancer
patients treated with neoadjuvant chemotherapy. Oncologist.
2007;12:636–43.
17. Hirata T, Shimizu C, Yonemori K, Hirakawa A, Kouno T,
Tamura K, et al. Change in the hormone receptor status following
administration of neoadjuvant chemotherapy and its impact on
the long-term outcome in patients with primary breast cancer. Br
J Cancer. 2009;101:1529–36.
18. De La Cruz L, Blankenship SA, Chatterjee A, Geha R, Nocera N.
Outcomes after oncoplastic breast-conserving surgery in breast
cancer patients: a systematic literature review. Ann Surg Oncol.
2016;23(10):3247–58. https://doi.org/10.1245/s10434-016-5313-
1. Epub 2016 Jun 29.
19. Chatterjee A Erban JK Neoadjuvant therapy for treatment of
breast cancer: the way forward, or simply a convenient option for
patients? Gland Surg. 2017;6(1):119–24. https://doi.org/10.2103
7/gs.2016.08.07.
20. Li ML, Dong Y, Luan SL, Zhao ZH, Ning FL. Changes of
expression of estrogen and progesterone receptors, human
epithelial growth factor receptor 2 and Ki-67 after neoadjuvant
chemotherapy in the treatment of breast cancer. J Biol Regul
Homeost Agents. 2016;30(4):1059–65.