(1)(8)F-FLT PETCT as an Imaging Tool for Early Prediction of Pathological Response in Patients With...

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ORIGINAL ARTICLE

18F-FLT PET/CT as an imaging tool for early prediction

of pathological response in patients with locally advanced breast

cancer treated with neoadjuvant chemotherapy: a pilot study

Flavio Crippa &Roberto Agresti &Marco Sandri &Gabriella Mariani &

Barbara Padovano &Alessandra Alessi &Giulia Bianchi &Emilio Bombardieri &

Ilaria Maugeri &Mario Rampa &Maria Luisa Carcangiu &Giovanna Trecate &

Claudio Pascali &Anna Bogni &Gabriele Martelli &Filippo de Braud

Received: 4 September 2014 /Accepted: 14 January 2015 / Published online: 12 February 2015# Springer-Verlag Berlin Heidelberg 2015

Abstract

P u r p o s e W e e v a l u a t e d w h e t h e r 18F -3 -d eo x y -3 -

fluorothymidine positron emission tomography (FLT PET)

can predict the final postoperative histopathological response

in primary breast cancer after the first cycle of neoadjuvant

chemotherapy (NCT).

MethodsIn this prospective cohort study of 15 patients with

locally advanced operable breast cancer, FLT PET evaluations

were performed before NCT, after the first cycle of NCT, and

at the end of NCT. All patients subsequently underwent sur-

gery. Variables from FLT PET examinations were correlated

with postoperative histopathological results.

ResultsAt baseline, median of maximum standardized up-

take values (SUVmax) in the groups showing a complete

pathological respons e (pCR) + residual cancer burden

(RCB) I, RCB II or RCB III did not differ significantly

for the primary tumour (5.0 vs. 2.9 vs. 8.9, p =0.293) or

for axillary nodes (7.9 vs. 1.6 vs. 7.0, p =0.363), whereas

the Spearman correlation between SUVmax and Ki67 pro-

liferation rate index was significant (r=0.69, p


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Introduction

Neoadjuvant chemotherapy (NCT) followed by surgery is a

standard therapeutic strategy for operable, locally advanced

breast cancer. Several clinical trials have demonstrated good

results, with an objective response rate of about 70 % and a

complete pathological response rate of up to 30 % [14].

These findings have led to improved surgical planning, anincreased rate of breast-conserving surgery even in patients

with an unfavourable tumour/breast size ratio before therapy,

and have enabled further evaluation of the biology of the

response of the primary tumour to chemotherapy and of the

efficacy of chemotherapy [5,6]. It is well known that the type

of pathological response after NCT is a fundamental prognos-

tic factor [512]. However, to date, the efficacy of NCT is

evaluated only upon final histology of the postsurgical speci-

men. Clinical examination and instrumental diagnostic tools,

such as mammography or ultrasound examination, based on

size and morphological criteria fail to predict early a complete

pathological response (pCR) to NCT and later to efficientlydistinguish responders from nonresponders [13]. Thus, there

is a need for a reliable method to assess the early response to

NCT in order to avoid ineffective and expensive therapy and

to provide alternative management options for consideration.

The use of MRI to search for new surrogate markers of

disease response has yielded interesting results in several stud-

ies that have evaluated the functional response to NCT in

breast cancer [14,15]. Some of these studies investigated the

utility of MRI in monitoring response to treatment by using

combined parameters such as diffusion-weighted MRI (DW-

MRI), dynamic contrast enhancement (DCE-MRI), volumet-

rics, and spectroscopy [1619].

PET using different tracers is playing an increasing role in

predicting the response of breast cancer to NCT [20]. At pres-

ent, 18F-fluorodeoxyglucose (FDG) PET is the most common-

ly used method for monitoring response of breast cancer to

treatment, according to published results [2129].

In the present study, we used 18F-fluorothymidine (FLT), a

tracer of proliferation [3032] tested in other pilot studies of

breast cancer [3236], to assess the value of FLT PET in the

early prediction of response of locally advanced operable

breast cancer to NCT and to identify its potential predictive

value based on relative changes in standardized uptake values

(SUV) of FLT PET in primary tumours and axillary nodes

after the first cycle of NCT.

Patients and methods

Patient population and treatment

This prospective cohort pilot study comprised patients with

potentially operable, locally advanced T2-3 breast cancer

treated with NCT followed by surgery at our institute.

Pretreatment histological diagnosis of invasive breast carcino-

ma was done by core needle biopsy in all patients and further

characterized for hormone receptor status, HER2 status and

prolif erativ e in dex. In it ial routine staging proced ures

consisted of clinical examination and mammographic and ul-

trasound evaluation of tumour size and axillary nodal status.

Chest plain radiography, whole-body bone scan and ultra-sound examination of the liver and abdomen were used to

assess distant metastases.

NCT consisted of an anthracycline/taxane-based regimen

for six cycles, with trastuzumab administered to those with

HER2-positive breast cancer. Specifically, the NCT regimen

included doxorubicin (60 mg/m2) + paclitaxel (200 mg/m2)

every 3 weeks for three cycles followed by cyclophospha-

mide/methotrexate/fluorouracil (600/40/600 mg//m2) on days

1 and 8 every 4 weeks for three cycles, and trastuzumab in

patients with HER2-positive breast cancer (8 mg/kg loading

dose decreased to 6 mg/kg) every 4 weeks for three cycles

concomitant with cyclophosphamide/methotrexate/fluorouracil.

Patients underwent breast-conserving surgery or total mas-

tectomy according to the clinical and instrumental response to

NCT, site of tumour inside the breast, cosmetic evaluation,

pr es en ce of ex te ns iv e in tr ad uc ta l co mp on en t an d/ or

multifocality. Axillary surgery (complete dissection or senti-

nel node biopsy) was performed based on clinical nodal status

before and after NCT. Nuclear medicine physicians, surgeons

and pathologists performed their work blinded to other results.

The institutional review board or equivalent approved this

study, and all subjects signed written informed consent.

PET evaluation

18F-3-Deoxy-3-fluorothymidine (FLT) was synthesized and

prepared by the Radiochemistry and Cyclotron Facility of our

Institute as previously described [37]. To minimize potential

pitfalls due to FLT metabolism, patients fasted for at least 6 h

before receiving approximately 3.5 MBq/kg of FLT adminis-

tered intravenously as a bolus, followed by 10 ml of normal

saline (0.9 % NaCl). Images were obtained 80 min after injec-

tion of FLT, in accordance with the work of Smyczek-Gargya

et al. [38] and with our previous unpublished studies on dif-

ferent tumours. A hybrid PET/CT system (64 TOF Gemini;

Philips Medical Systems) was used in the present study.

During the waiting period, patients were asked to drink 0.5 l

of water to reduce bladder activity and radiation exposure to

the bladder and to use the bathroom 30 min after FLT admin-

istration and immediately before the start of the PET study.

The imaging protocol included a CT scout scan to define the

axial imaging range (from upper thigh to skull base), a low-

dose CT scan without contrast enhancement, and lastly, a

three-dimensional PET scan (3 min per bed position). CT

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images, obtained with the patient breathing shallowly,

were used for attenuation correction of the PET data

and anatomical positioning of the FLT findings. Each

patient was studied before therapy (time-point t0), after

one cycle of chemotherapy (time-point t1) and after

completion of therapy (time-point t2), about 1 month

before surgery. Figure 1 shows the flow chart of the

study with the three FLT PET evaluations.Using dedicated PET workstations (Philip Extended

Brilliance Workspace), nuclear medicine physicians

blinded to each patients history and clinical and con-

ventional imaging findings visually analysed the PET/

CT images, looking especially for areas of focally in-

creased FLT uptake in the breast tumour and ipsilateral

axillary regions. FLT uptake was evaluated semiquanti-

tatively using the SUVmax defined as the highest SUV

in a region of interest and calculated as: SUV= (tissue

activity in megabecquerels per gram)/(injected activity

in megabecquerels)/(body weight in grams). SUVmax

was measured in the primary breast tumour (SUVTmax)and, when detectable, in the dominant axillary lymph

node (SUVNmax) lesions, the latter defined as the largest

lymph node and the highest FLT uptake among the de-

tectable nodes in the fused PET/CT images. During the

course of NCT, changes in SUVmax in target lesions

were monitored by comparing FLT uptake at time points

t0, t1 and t2, and the results are expressed as absolute

value and relative percentage change in SUVmax:

SUVmax ti 100 SUVmax ti SUVmax t0 .

SUVmax t0

wherei is 1 or 2.

Pathological examination and evaluation criteria

To assess pathological response, we opted for the web-based

MD Anderson Residual Cancer Burden (RCB) calculator

[39]. This method, proposed by Symmans et al. [8], allows

c a l c u l a t i o n o f a n i n d e x t h a t c o m b i n e s p a t h o l o g y

measurements of the primary tumour (size and cellularity)

and nodal metastases (number and size):

RCB index1:4 finvdprim 0:17 4 10:75LN dmet

0:17

where finv is the proportion of the primary tumour bed that

contains invasive carcinoma, LN is the number of axillary

lymph nodes containing metastatic carcinoma, dmetis the di-ameter of the largest metastasis in an axillary lymph node, and

dprimffiffiffiffiffiffiffiffiffiffid1d2

p whered1andd2are the bidimensional diame-

ters of the primary tumour bed in the resection specimen [8].

Using two cut-off points, the authors proposed four RCB

categories (RCB 0, RCB I, RCB II and RCB III) correspond-

ing to pCR, minimal residual disease (near-complete re-

sponse), moderate residual disease, and extensive residual dis-

ease, respectively (Table1).

In addition, based on our previous experience, we chose a

cut-off level of 3 for the RCB index, since this value,

contained in the RCB II class (moderate response), may rep-

resent the threshold separating patients with RCB II into those

who show a partial response and are closer to RCB I patients

and those with a partly nonresponding large tumour in pro-

gression. Hence, this cut-off allowed the study population to

be split into two groups: complete/partial responders and

complete/partial nonresponders.

All pathological assessments and immunohistochemistry

were performed at the Pathology Unit of our institute.

Surgical specimens were fixed in neutral formalin and embed-

ded in paraffin, and sections were stained with haematoxylin

and eosin at 4 C. Tumour grade was assessed according to the

procedure of Elston and Ellis [40]. Immunohistochemistry for

oestrogen receptor (ER), progesterone receptor (PgR) and hu-

man epidermal growth factor receptor 2 (HER2) was per-

formed on 4-m-thick sections of breast cancer resection

specimens, whereas immunostaining for Ki67 was performed

on both breast cancer resection specimens and metastatic

axillary lymph nodes. Staining for ER (clone SP1,

Ventana), PgR (clone SP2, Ventana), HER2 (p185,

Dako, diluted 1:1,000), Ki67 (MIB1, Dako, diluted

Fig. 1 Flow chart of the study. The neoadjuvant chemotherapy (NCT)regimen comprised doxorubicin + paclitaxel for three cycles (grey

squares) followed by cyclophosphamide/methotrexate/fluorouracil for

three cycles (white squares). SUVmax(t1) and SUVmax(t2) arerelative percentage changes in SUVmax measured at t1 and t2 for theprimary breast tumour and for the dominant axillary lymph node

820 Eur J Nucl Med Mol Imaging (2015) 42:818830


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1:100) was detected using an OPTIview DAB detection

system on a Ventana Ultra benchmark Autostainer.

Positive staining for ER and PgR was defined as nucle-

ar staining in 1 % of the tumour cells, whereas HER2

was assessed based on the intensity of tumour cell

membrane staining, scored as 0 (negative), 1+ (weak),

2+ (moderate) and 3+ (strong) staining in at least 30 %

of the tumour cells. The Ki67 proliferation index of

each case was evaluated based on the percentage of

Ki67-positive cells among at least 200 tumour cells.Our pathological reports included an explicit statement

concerning assessment for the presence and degree of

response to chemotherapy.

Statistical analysis

The hypothesis thatkindependent samples come from popu-

lations with the same median was tested using the Kruskal-

Wallis nonparametric rank test. Differences were considered

significant atp0.05.

A linear score based on relative percentage change in

maximum SUV att1in the primary tumour and in the domi-

nant axillary node was proposed for predictive purposes:

SUVTmax t1 SUVNmax t1

where the coefficients, and were estimated using a linear

regression model withSUVTmax(t1) andSUVNmax(t1) as

explanatory variables and the RCB index as outcome variable.

The predictive powers ofSUVTmax(t1), SUVNmax(t1)

and of thescore were assessed by estimating the area under

the ROC curve (AUC). The 95 % confidence intervals (CI) for

AUC and the Pvalue of the test of the null hypothesis that

AUC=0.5 (no predictivity) were estimated using bootstrap

methods with 1,000 replications. Overall accuracy, sensitivity,

specificity, and positive and negative predictive values (PPV

and NPV, respectively) were also estimated for some cut-off

values of the two parameters.

Statistical analyses were performed using Stata13

(StataCorp, College Station, TX) and R (version 3.1.2; R

Foundation for Statistical Computing, Vienna, Austria)

software.

Results

From October 2011 to January 2013, 15 T2-3 N0-1 patients

were accrued to the present study. The median age was

42 years (range 29 63 years). All patients underwent the

three scheduled scans. Figure2shows an example of the im-

aging of the breast tumour and axillary involved nodes on the

baseline FLT PET scan (time t0; Fig.2a), and the progressiveresponse to NCT on the interim (time t1) and final (time t2)

scans compared with baseline (Fig.2b). All patients tolerated

the PET scanning protocol well and all breast lesions were

visualized by FLT PET.

All but one patient, who exhibited progressive dis-

ease after the first three cycles of the doxorubicin/

pa cl it ax el re gi me n, co mp le te d th e sc hedu le d NC T.

Consistent with protocol indications, five patients with

HER2 amplification received trastuzumab. All patients

underwent breast surgery and axillary surgery. Eight pa-

tients underwent total mastectomy (in two due to

microcalcifications with multicentric foci of intraductaldisease), two underwent nipple-sparing mastectomy

(based on breast size and the site of the tumour in order

to achieve the best cosmetic result), and five underwent

quadrantectomy). Ten patients underwent complete axil-

lary dissection, two sentinel node biopsy followed by

axillary dissection, and three sentinel node biopsy only.

Pathological evaluation of surgical specimens according

to previously described classifications [39] identified six

high responders (RCB 0 or RCB I), five weak re-

sponders (RCB II) and four nonresponders (RCB III).

Table2summarizes the clinical, radiological and path-

ological characteristics of the entire patient cohort and

of the three RCB groups at t0. Furthermore, breast can-

cer subtype in all patients was also classified according

to the consensus of the St Gallen International Expert

Panel members [41]. The baseline characteristics of pri-

mary tumours did not differ significantly among the

RCB groups, except for the Ki67 proliferation index.

The mean postoperative pathological tumour size was

15.5 mm (range 0 40 mm) in the entire patient co-

hort, whereas, consistent with the RCB classification,

tumour size differed greatly between the RCB 0 +

RCB I group (3.5 mm) and the other two RCB groups

(RCB II 23.6 mm, RCB III 23.3 mm), as did the rates

of postoperative histologically negative axillary nodes,

where rates were higher in the RCB 0 + RCB I group

(66.7 %) than in the RBC II group (40.0 %) and the

RCB III group (0.0 %).

Table3summarizes the median FLT PET SUVmaxatt0,t1andt2 and the relative percentage changes att1 and t2 in the

primary tumours and in the axillary nodes in the three RCB

groups. The median time (with range) of the interval between

first chemotherapy and PET at baseline was 15 (1 29) days;

Table 1 RCB categories for classification of residual disease in thebreast and axillary nodes after neoadjuvant chemotherapy

RCB class RCB index Amount of disease

0 0 Pathological complete response

I 0 1.36 Minimal residual disease

II 1.36 3.28 Moderate residual disease

III > 3.28 Extensive residual disease



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the median time of PET t1 after the first cycle of chemotherapy

was 18 days (12 21 days); the median time of PET t2after

the last cycle of chemotherapy (before surgery) was 12 days

(5 27 days).

At baseline, median SUVmax values of the primary

tumours for the RCB 0 + RCB I, RCB II and RCB

III groups were 5.0, 2.6, and 8.4, respectively, and of

the axillary nodes were 7.9, 0.8, and 3.2, respectively

(Table 3). S p earmans c o rr e la t i on a t t0 between

SUVTmax and Ki67 proliferation index was positive,

strong and statistically significant (r=0.69, p


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3. Patients with an RCB index below the threshold level 3(RCB 0+I+partly-responding RCB II) vs. patients with

RCB index >3

The results showed that the two parameters play a

different role in the identification of the RCB response

(Fig. 5). On the one hand, the predictive power of

SUVTmax(t1) was good and statistically significant

for identifying RCB 0 + RCB I responses (AUC 0.91,

95 % CI 0.72 1.00, p52.9% (i.e. a reduction in SUVTmax less

than 52.9 %), SUVNmax(t1) showed excellent accuracy inidentifying subjects with a RCB index above 3 (AUC 1.00,

Table4). In addition, SUVNmax(t1) had an interesting (al-

though not statistically significant) ability to separate subjects

withSUVTmax(t1)>52.9% into two groups: the group of

RCB III patients and a heterogeneous group that included

RCB I and RCB II patients with delayed response to chemo-

therapy, clinically node-negative patients, and those with a

low-proliferating luminal A tumour (AUC 0.77, p=0.119).

The cut-off value SUVNmax(t1)18.0% (i.e. a reduction

in SUVNmaxgreater than or equal to 18.0 %) can be used in

the subgroup with SUVTmax(t1)>52.9% for the identifica-

tion of RCB III patients.Lastly, a predictive score based on SUVTmax(t1) and

SUVNmax(t1) parameters was calculated:

= 0.043SUVTmax(t1)0.013SUVNmax(t1) +

3.060

This score showed good predictive power for all three dis-

crimination problems considered, with AUC 0.94 (pT2 5 (33.3) 3 (50.0) 1 (25.0) 1 (20.0)

Oestrogen receptor,n(%)

Negative 9 (60.0) 5 (83.3) 2 (50.0) 2 (40.0)

Positive 6 (40.0) 1 (16.7) 2 (50.0) 3 (60.0)

HER2,n(%)

Negative 10 (66.7) 2 (33.3) 4 (100.0) 4 (80.0)

Positive 5 (33.3) 4 (66.7) 0 (0.0) 1 (20.0)

Grade,n (%)

2 6 (40.0) 1 (16.7) 2 (50.0) 3 (60.0)

3 9 (60.0) 5 (83.3) 2 (50.0) 2 (40.0)

Nodal involvement (cN),n(%)

Negative 6 (40.0) 4 (66.7) 2 (50.0) 0 (0.0)

Positive 9 (60.0) 2 (33.3) 2 (50.0) 5 (100.0)

Breast cancer subtype, n(%)a

Basal-like 9 (60.0) 5 (83.3) 2 (50.0) 2 (40.0)

Luminal-like 6 (40.0) 1 (16.7) 2 (50.0) 3 (60.0)

aClassified according to the consensus of the St Gallen International Expert Panel members [29]



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Discussion

PET may be a major noninvasive imaging modality for eval-

uating cancer cell proliferation, one of the most important

biological features of malignancies [42]. In this regard, the

most promising PET tracer is currently FLT, a fluorine-

modified thymidine analogue. FLT is phosphorylated by thy-

midine kinase-1 and is not incorporated during DNA synthe-

sis, instead becoming trapped within proliferating cells using

the salvage pathway for DNA synthesis [30,31]. It is widely

accepted that FLT is a marker of cells in the S-phase of the cell

cycle, suggesting its ability to reflect tumour aggressiveness

and response to therapy [30,31,43]. The uptake of FLT has

been linked to cell proliferation rate and has been used to

study proliferation in lymphomas, and breast and lung tu-

mours [4446]. We have also found a significant association

between FLT uptake and Ki67 proliferation index [47] in our

series.

FLT PET has often been compared with FDG PET in the

visualization, diagnosis and staging of several tumour types,

including those of the lung, head and neck, stomach, oesoph-

agus, brain and breast [4853]. In general these clinical studies

demonstrated that tumour uptake of FLT is generally lower

than that of FDG, but it can provide high sensitivity and major

Table 3 SUVmax(median and range) in primary tumours (SUVTmax)and axillary nodes (SUVNmax) after FLT PET scans att0, t1 and t2by RCBgroup, and relative percentage changes in SUVmax(median and range) at

t1 an d t2 in primary tumours (SUVTmax) and axillary nodes(SUVNmax) by RCB group

Predictor Total RCB 0 + RCB I RCB II RCB III pvaluea

SUVTmax

t0 4.0 (1.5 12.1) 5.0 (3.4 10.9) 2.6 (1.5 4.4) 8.4 (2.9 12.1) 0.105

t1 2.6 (1.4 10.5) 2.2 (1.5 4.6) 2.2 (1.4 4.0) 6.2 (1.6 10.5) 0.305t2 0.9 (0.0 9.9) 0.0 (0.0 0.0) 1.3 (0.0 3.4) 5.8 (0.9 9.9) 0.005

SUVTmax

t1 26.2 (80.8 12.9) 55.8 (80.8 11.8) 7.9 (18.8 5.3) 26.2 (44.8 12.9) 0.019

t2 69.0 (100.0 18.2) 100.0 (100.0 100.0) 45.0 (100.0 22.7) 26.2 (69.0 18.2) 0.007

SUVNmax

t0 2.8 (0.0 25.6) 7.9 (1.4 11.2) 0.8 (0.0 2.8) 3.2 (1.0 25.6) 0.128

t1 2.1 (0.0 9.8) 2.7 (1.1 5.7) 0.0 (0.0 3.5) 1.7 (0.0 9.8) 0.201

t2 1.0 (0.0 7.4) 0.7 (0.0 2.3) 0.0 (0.0 2.6) 2.2 (0.0 7.4) 0.285

SUVNmax

t1 46.9 (100.0 25.0) 55.5 (69.5 0.0) 1.0 (100.0 25.0) 46.9 (100.0 18.8) 0.321

t2 69.4 (100.0 37.5) 92.3 (100.0 0.0) 3.1 (100.0 1.0) 69.4 (100.0 37.5) 0.343

aKruskal-Wallis test

Fig. 3 Relative percentagechanges in SUVmaxatt1andt2forthe primary breast tumour[SUVTmax(t1) andSUVTmax(t2)] and the dominantaxillary lymph node[SUVNmax(t1) andSUVNmax(t2)] in each patient,together with their median valuesfor each RCB group. a

SUVTmax(grey lines) andmedianSUVTmax(black lines).bSUVNmax(grey lines) andmedianSUVNmax(black lines)



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specificity because, unlike FDG, it does not accumulate in

areas of inflammatory alteration potentially associated with

cancer therapy, leading to false-positive findings [32, 54].

For staging FLT is of limited value because of its high phys-

iological uptake in the liver and bone marrow and consequentpossible false-negative results in the detection of distant me-

tastases at those sites [32,55].

The potential value of PET in monitoring response to NCT

in breast cancer has been evaluated. However, these studies

were mainly done with FDG PET, with only a few involving

FLT PET in heterogeneous series of patients with different

disease stages, chemotherapeutic regimens and scan

acquisition protocols. In one of these studies, Pio et al. evalu-

ated 14 patients with primary or metastatic breast cancer who

were starting a novel chemotherapy or hormonal therapeutic

regimen, and who underwent sequential FLT PET scans.

Although there were strong clinical and therapeutic differ-ences, FLT PET uptake after the first course of chemotherapy

was significantly correlated with overall response in terms of

late changes in CA27.29 tumour marker levels and tumour

size as measured by CT [33]. In another study in 13 patients

with stage IIIV breast cancer, the response to the 5-fluoro-

uracil/epirubicin/cyclophosphamide (FEC) regimen was eval-

uated by FLT PET performed at baseline and 1 week after the

Fig. 4 Scatter plot of the relativepercentage changes in SUVmaxatt1for the primary breast tumour(SUVTmax) and for thedominant axillary lymph node(SUVNmax) in each patient,with their corresponding RCBgroup and RCB index (inparentheses)

Table 4 Predictive ability ofSUVTmax(t1), SUVNmax(t1) and of the proposed score for three discriminating problems: identification ofpCR +RCB Ipatients, RCB IIIpatients, and patients with RCB index below/above 3

RCB 0+I vs. RCB II+III RCB III vs. RCB 0+I+II RCB index 3

AUC pvaluea AUC pvaluea AUC pvaluea

SUVTmax(t1) 0.91 (0.72 1.00) 52.9 %

0.77 (0.45 1.00) 0.119 1.00

scoreb 0.94 (0.82 1.00)


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first cycle, considering uptake at 90 min and the irreversible

trapping of FLT as the reference parameters. FLT PET was

able to discriminate between clinical response and stable dis-

ease [34]. In a further study the value of FLT PET was inves-

tigated by measuring the early response to docetaxel chemo-

therapy. This study was performed in 20 patients with stage

IIIV breast cancer who were unresponsive to first-line che-

motherapy or progressing on previous therapy, and FLT PET

was performed after the first or the second cycle. Although the

patient population was nonhomogeneous, the PET response

was assessed after two cycles in six patients (compared with

one cycle in the rest), and clinical and instrumental criteria

were used to define response rather than histopathology,

changes in the FLT PET signal were nonetheless predictive

of response to therapy (sensitivity 0.85, specificity 0.80) [35].

More recently, Woolf et al. evaluated 20 patients with locally

advanced breast cancer who underwent FLT PET before and

after the first cycle of a FEC or FEC + docetaxel (FEC-T)

chemotherapy regimen [36]. However, in this series, although

a significant and strong correlation between Ki67 and SUVmaxwas found, neither baseline SUVmaxnorSUVmaxfrom FLT

PET was predictive of response after the first cycle of treat-

ment. Homogeneous SUVmaxreduction in most patients was

the main concern in that study.

At present, there are no definitive indications regarding the

optimal timing of PET after FLT injection [36,38,56]. In our

study, we used static PET imaging acquisitions at 80-min in-

tervals and the semiquantitative SUV method to measure tu-

mour FLT uptake. This is a simple and widely adopted proce-

dure for PET imaging in clinical protocols, providing a sum

total measure of the tumour tracer uptake by metabolic trap-

ping [57]. SUV can be less precise than PET analysis based on

dynamic image acquisitions and kinetic modelling, because it

does not account for the possible contribution of labelled me-

tabolites and perfusion. Nevertheless, in several clinical stud-

ies FLT SUV was significantly correlated with cell prolifera-

tion [5860] and our study aimed to evaluate a method avail-

able in a clinical setting.

This pilot study showed that FLT PET might serve in the

construction of a prediction rule able to discriminate early

between two different populations of patients undergoing

NCT based on the probability of response to the therapy. In

Fig. 5 ROC curves ofSUVTmax(t1) (a,b) and score(c, d;= 0.043SUVTmax(t1)0.013SUVNmax(t1)+3.060)for discriminating pCR+RCB Isubjects (a,c) and not RCB III(i.e. pCR+RCB I and II)subjects (b,d); the main cut-offvalues are plotted on the curves



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particular, a joint analysis of variations in SUVmaxin the pri-

mary tumour and the axillary lymph nodes appears to identify

early mammary tumours will achieve pCR or near pCR (RCB

I) on final histology. The ability to predict early response after

one or two cycles of NCT would avoid unnecessary toxicities

in patients with an unsatisfactory response, with a potential

impact on clinical outcomes and quality of life.

Our results showed that at t1, FLT PET identified threedifferent patient populations: a group with a high rate of re-

sponse both in tumour and axillary nodes; a group with an

initial response at the axillary node level without a similar

final response in the tumour; and a heterogeneous group with

a low rate of response at both levels due to a low-proliferating

luminal A tumour or a clinically node-negative tumour with

delayed response to NCT. Notwithstanding this interesting

ability to identify different populations, SUVTmax(t1) and

SUVNmax(t1) showed substantially different predictive

roles: SUVTmax(t1) seemed able to discriminate between

responders and all other patients, whereasSUVNmax(t1) dis-

criminated between complete nonresponders and moderate/partial responders within the nonresponder group. In addition,

the two parameters may be used to develop a single score with

a significant ability to identify responders, partial responders

and nonresponders.

One crucial issue is the optimal time for performing the

PET scan to evaluate response to NCT. A recent meta-

analysis has shown that the predictive value of FDG PETearly

after therapy (after the first or second cycle of NCT) is signif-

icantly better than after three or more cycles [61], possibly

because PET detects metabolic or proliferative changes in

the tumour before other clinical or radiological tools are able

to detect tumour size shrinkage. In our study, after the baseline

FLT PET att0, we chose to perform the subsequent PET scans

3 weeks after the first cycle of NCT (time t1, immediately

before the second cycle) and at the end of therapy (timet2).

Another crucial point is the definition of a method to eval-

uate the response after NCT. It is well known that the patho-

logical measurement of residual cancer after NCT is an impor-

tant prognostic factor that can influence patient outcome [20].

Recently, a meta-analysis of almost 12,000 patients accrued in

12 international trials has shown that pCR is a valid surrogate

endpoint of long-term clinical benefit, particularly in aggres-

sive tumour subtypes [62]. Consequently, the definition of an

effective method for measuring the percentage of residual dis-

ease [12] and the correct interpretation of the results [63] is

fundamental. In the study NSABP B18, classification was

based on the simple dichotomy between pCR and pINV (his-

tological evidence of less residual invasive carcinoma) [1],

whereas Sataloff et al. [7] graded the response according to

four categories ranging from a total or near-total therapeutic

effect (grade A) to no therapeutic effect (grade D) as assessed

based on microscopic changes such as necrosis, calcifications,

fibrosis and inflammatory infiltration. Ogston et al. [64]

proposed a five-step scale of response based on the progres-

sive reduction in tumour cellularity in the breast only. Finally,

Chollet et al. [65] proposed a new classification based on

residual disease in the breast and nodes (RDBN), which how-

ever is only applicable to patients who have undergone axil-

lary dissection and for discriminating between responders and

nonresponders [66]. As discussed above, we opted for the

web-based MD Anderson RCB calculator [39], which waspreviously defined by Symmans et al. [8] for the evaluation

of response to NCTusing routine pathological features such as

the largest two dimensions (measured in millimetres) of the

tumour bed, percentage of cellularity of the tumour and

intraductal disease, number of nodal metastases, and size of

the largest nodal metastasis. In our opinion, this four-group

RCB classification, that gives an accurate calculated value for

each patient, allowed the best evaluation of response for sta-

tistical analysis.

Until now, response of breast cancer to NCT has usually

been evaluated in clinical studies with FDG PET. One of the

first studies evaluated 47 patients treated with different che-motherapy regimens, and FDG PET predicted pCR with a

sensitivity of 91 % and a specificity of 86 % [21 ].

Interestingly, in multivariate analysis SUV appeared to be

the only predictive factor of pCR. A further study confirmed

the significant value of FDG PET in predicting response to

NCT (sensitivity 77 %, specificity 80 %, AUC 0.82) in 50

patients treated with a more homogeneous chemotherapy reg-

imen, considering the changes in SUVmaxbetween baseline

and after the second cycle of chemotherapy [22].

More recently, several studies have assessed the predictive

value of FDG PET in different molecular subtypes of breast

cancer. Groheux et al. studied the response to NCT in terms of

FDG uptake in patients with stage II/III HER2-positive breast

cancer [23] and triple-negative breast cancer [24]. In the first

group of 30 HER2-positive patients, using a homogeneous

chemotherapy regimen, ROC analysis showed that the best

predictive result in terms of pCR after two cycles of chemo-

therapy was characterized by an AUC of 0.91, with a sensi-

tivity of 86 % and a specificity of 94 %. This highlights the

ability of FDG PET to identify the group of patients without

pCR [23]. Similarly, in a second group of 50 triple-negative

patients, FDG PET was performed before treatment and after

two cycles of chemotherapy, and theSUVmax in the primary

tumour was the most effective parameter for predicting pCR

(AUC 0.84) [24].

Koolen et al. have also found that FDG PET is of value in

predicting pathology outcomes after NCT in triple-negative

breast cancer [25], but this was not confirmed by Humbert

et al. [26]. In the former study, 98 T2-3 breast cancer patients

underwent FDG PET before treatment and after 6 8 weeks of

NCT, and FDG PET showed different predictive power in the

three molecular subtypes: HER2-positive (AUC 0.35), ER-

positive/HER2-negative (AUC 0.90) and triple-negative



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(AUC 0.96). These results in triple-negative patients have also

been confirmed in a larger series [27]. Humbert et al. exam-

ined 136 T2-3 breast cancer patients who were treated with

wide variety of chemotherapy regimens, and investigated the

levels of FDG uptake and metabolic changes after the first

cycle of NCT in patients with the same molecular subtypes.

They found that pCR has significant predictive value only in

HER2-positive breast cancer [26].In a substudy of the NEOALTTO trial in Her2-positive

breast cancer patients, Gebhart et al. found that early metabol-

ic assessment using FDG PET (2 and 6 weeks after the start of

anti-HER2 treatment) is able to identify patients with an in-

creased likelihood of pCR [28]. Increased likelihood of pCR

was associated with higherSUVmax at both time-points used

in the study. However, it is noteworthy that there was marked

heterogeneity in response in terms of FDG uptake according

to hormonal receptor status, with hormonal receptor-positive

tumours showing a significantly lower frequency of pCR.

The value of FDG as a metabolic tracer may be more af-

fected by several different molecular crosslinks and crosstalk,as well as metabolic differences in molecular breast cancer

subtypes, and especially in glycolytic metabolism [6769].

The metabolic differences among the distinct immunohisto-

chemical breast cancer subtypes has been related to specific

metabolic patterns [70].

MRI, alone or associated with FDG PET, has been also

investigated as a non-invasive technique for monitoring the

response to NCT and for assessment of residual disease. A

meta-analysis of the diagnostic performance of DW-MRI

and DCE-MRI in terms of the pathological response to NAC

in patients with breast cancer has been performed. The esti-

mated sensitivity and specificity of DW-MRI were 93 % and

82 %, respectively. In contrast, the sensitivity and specificity

of CE-MRI were 68 % and 91 % [71]. Based on these results,

t h e c o m b i n e d u s e o f D W - M R I a n d C E - M R I a s a

multiparametric evaluation has the potential to improve the

diagnostic performance in monitoring NCT. In this regard,

by applying multiparametric DCE-MRI and DW-MRI some

authors have found a sensitivity, specificity and AUC of 92 %,

78 % and 0.88, respectively, in predicting pathological re-

sp o n se after th e first cy cle o f ch emo th erap y [16 ].

Furthermore, several studies have investigated the usefulness

of MR spectroscopy for predicting response to therapy. The

discriminative value of this technique is still under investiga-

tion due to the difficulty in quantifying choline [18,19], espe-

cially following the central changes in morphology and vas-

cularity induced by chemotherapy.

More recent studies have investigated the possible value of

the combination of MRI and FDG PET [17,72, 73]. Both

techniques can provide functional information with MRI,

when evaluating angiogenesis, mainly giving information

about volume, perfusion and the permeability index, and

FDG PET reflecting the metabolic changes of breast cancer.

In particular, in a single institutional study of 93 breast cancer

patients treated with NCT, Pengel et al. showed that FDG PET

and MRI have a complementary predictive ability. Using FDG

PET and MRI together in a multivariate analysis combined

with breast cancer subtypes, the AUC was 0.90 [72].

Despite its better accuracy than conventional radiological

techniques, even MRI may encounter difficulties especially in

patients with a non-mass lesion. In these patients, there is noboundary volume at presentation and the response to ther-

apy cannot follow a concentric shrinkage, although resid-

ual disease is most likely represented by scattered foci of

enhancement [74].

Our pilot study with FLT PET was performed in a small

patient population and clearly needs to be repeated in a larger

cohort to definitively assess and validate the estimated cut-off

values and the proposed prediction rule. Further studies are

also needed to evaluate the impact of different molecular

breast cancer subtypes and subgroups with different prolifer-

ation rates, if any, on the predictive ability of FLT PET.

However, our study provided interesting results in terms ofsensitivity, specificity and AUC compared with previous stud-

ies of FDG PETand/or MRI. The preliminary findings suggest

the potential utility of PET scans for early monitoring of the

response to NCT in order to choose a therapeutic strategy with

a greater probability of efficacy rather than unexpected futility.

Conflicts of interest None.

Funding This work was supported by a grant from AssociazioneItaliana Ricerca sul Cancro (Study INT/35/10).

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