Dedicated breast PET for detecting residual disease after neoadjuvant chemotherapy in operable breast cancer: A prospective cohort study

Accepted Manuscript Dedicated breast PET for detecting residual disease after neoadjuvant chemotherapy in operable breast cancer: A prospective cohort study Shinsuke Sasada, Norio Masumoto, Noriko Goda, Keiko Kajitani, Akiko Emi, Takayuki Kadoya, Morihito Okada PII:

S0748-7983(18)30044-1

DOI:

10.1016/j.ejso.2018.01.014

Reference:

YEJSO 4829

To appear in:

European Journal of Surgical Oncology

Received Date: 14 November 2017 Revised Date:

10 December 2017

Accepted Date: 7 January 2018

Please cite this article as: Sasada S, Masumoto N, Goda N, Kajitani K, Emi A, Kadoya T, Okada M, Dedicated breast PET for detecting residual disease after neoadjuvant chemotherapy in operable breast cancer: A prospective cohort study, European Journal of Surgical Oncology (2018), doi: 10.1016/ j.ejso.2018.01.014. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Original article

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Dedicated breast PET for detecting residual disease after neoadjuvant chemotherapy in

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operable breast cancer: A prospective cohort study

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Shinsuke Sasada, Norio Masumoto, Noriko Goda, Keiko Kajitani, Akiko Emi, Takayuki Kadoya,

Morihito Okada

Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine,

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Total word count: 1,883

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Hiroshima University, Hiroshima, Japan

Correspondence to:

Shinsuke Sasada

Department of Surgical Oncology

Research Institute for Radiation Biology and Medicine, Hiroshima University

1-2-3 Kasumi, Minami-Ku, Hiroshima City, Hiroshima 734-8551, Japan

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Tel: +81-82-257-5869

Fax: +81-82-256-7109

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E-mail: [email protected]

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Abstract

Purpose: Diagnostic methods to evaluate the response to neoadjuvant chemotherapy (NAC) for

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breast cancer have not been established. Dedicated breast PET (DbPET) is a high-resolution

molecular breast imaging method, and we investigated the capability of DbPET to predict

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residual primary tumors after NAC compared with whole-body PET (WBPET).

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Methods: Forty-five patients (47 tumors) underwent WBPET and ring-type DbPET after NAC,

and the tumors were completely resected between January 2016 and March 2017. The

pathological response was classified as complete remission (ypT0), residual intraductal disease

(ypTis), or residual invasive disease (ypT≥1). Standardized uptake value (SUV) and

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tumor-to-normal tissue ratio (TNR) were assessed.

Results: Twelve patients achieved ypT0 and five developed ypTis. DbPET detected all cases of

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ypTis, and WBPET detected only one case of ypTis. The sensitivity, specificity, and accuracy of

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WBPET for ypTis and/or ypT≥1 were 54.3%, 83.3%, and 61.7%, respectively, and those of

DbPET were 77.1%, 83.3%, and 78.7%, respectively. In the ypT0/ypTis/ypT≥1 groups, the

median WBPET-SUV, DbPET-SUV, and DbPET-TNR was 1.0/0.9/1.1, 1.7/1.8/2.2, and

1.0/1.6/1.7 (P = 0.134, 0.077, and 0.008), respectively. Areas under the curves of WBPET-SUV,

DbPET-SUV, and DbPET-TNR for predicting ypTis and/or ypT≥1 were 0.610, 0.648, and 0.807,

respectively.

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Conclusions: DbPET was more accurate than WBPET in detecting residual primary tumors

after NAC, particularly intraductal carcinoma. TNR was the better parameter for pathological

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evaluation compared with SUV.

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Keywords: breast cancer; dedicated breast PET; FDG; neoadjuvant chemotherapy; response

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Abbreviations

CI: confidence interval

CT: computed tomography

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DbPET: dedicated breast positron emission tomography

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AUC: area under the curve

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FDG: F-fluorodeoxyglucose

FOV: field of view

HER2: human epidermal growth factor receptor 2

IQR: interquartile range

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MRI: magnetic resonance imaging

NAC: neoadjuvant chemotherapy

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pCR: pathological complete response

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PEM: positron emission mammography

PET: positron emission tomography

SUV: standardized uptake value

TNR: tumor-to-normal tissue ratio

US: ultrasonography

WBPET: whole-body positron emission tomography

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Introduction

Breast cancer is the most common cancer affecting adult women worldwide[1]. Postoperative

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adjuvant chemotherapy has shown to reduce the recurrence of breast cancer and mortality

rates[2]. Studies have shown that neoadjuvant chemotherapy (NAC) results in a comparable

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prognosis with that of adjuvant chemotherapy[3, 4]. In addition, pathological complete response

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(pCR) after NAC provides patients with better survival benefit[4, 5].

Although some modalities used to assess the response after NAC, such as

ultrasonography (US)[6], enhanced magnetic resonance imaging (MRI)[7], and whole-body

positron emission tomography (WBPET) using

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F-fluorodeoxyglucose (FDG)[8] are being

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studied, no standard examination method has been established. Dedicated breast PET (DbPET)

is a newly developed method for diagnosing breast diseases and has two scanner types:

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opposite and ring[9]. One of the benefits of using the DbPET detector is that it can be placed

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close to the breast; the influence of respiratory movement is minimal because body surface

imaging is smaller than that with WBPET. The opposite-type DbPET, such as positron emission

mammography (PEM), has higher spatial resolution and sensitivity for breast imaging than

WBPET[10].

We hypothesized that DbPET was more suitable for detecting residual breast tumor

after NAC, particularly intraductal and microinvasive disease, than WBPET. Only one report of

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therapeutic assessment of PEM in NAC has been published[11], and the diagnostic capability of

ring-type DbPET has not been reported. Unlike the opposite type, the ring-type DbPET can

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calculate the standardized uptake value (SUV). Because the opposite type DbPET does not

obtain 3-dimensional images, and attenuation and scatter correction cannot be performed, SUV

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cannot be calculated accurately [12]. Therefore, we investigated the capability of ring-type

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DbPET to detect residual primary breast tumor after NAC compared with WBPET.

Patients and Methods

Patients

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Among consecutive patients with operable breast cancer who underwent NAC and complete

resection between January 2016 and March 2017 at the Hiroshima University Hospital, those

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who received preoperative WBPET and DbPET were included in this study. NAC was

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administered after pathological assessment of biopsy specimens. NAC regimens consisted of

anthracycline- and taxane-based chemotherapeutics, and trastuzumab was added for human

epidermal growth factor receptor 2 (HER2)-positive disease. The Institutional Review Board of

the Hiroshima University Hospital approved this study. All procedures performed involving

human participants were in accordance with the ethical standards of the institutional research

committee and with the 1964 Helsinki Declaration and its later amendments or comparable

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ethical standards. For this prospective cohort study, the need for formal consent was waived.

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WBPET and DbPET examinations

WBPET examinations were performed 1 h after a 3–3.7 MBq/kg FDG injection was administered

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with an integrated Discovery ST16 PET/computed tomography (CT) scanner (GE Healthcare,

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Little Chalfont, UK; BGO/6.25 × 6.25 × 30 mm). Low-dose non-enhanced CT images (3- to 4-mm

thick sections) for attenuation correction and localization of lesions identified using PET were

obtained from the head to the pelvic floor of each patient according to a standard protocol.

Immediately after CT, the identical axial field of view (FOV) (154 mm) was scanned using PET for

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2–3 min per table position depending on the patient condition and the scanner performance. The

acquired data were reconstructed as 128 × 128 matrix images (pixel size, 4.7 × 3.25 mm) using

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Fourier rebinning and ordered-subset expectation maximization algorithms. Both PET and CT

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studies were performed with the patient under normal tidal breathing.

Immediately after WBPET, DbPET scans were obtained while patients were in the

prone position, by using an Elmammo scanner (Shimadzu, Kyoto, Japan; LGSO/1.44 ×1.44 × 18

mm). The FOV was 185 × 156.5 mm; the scan time was 7 min per bed position. The data were

reconstructed using a 3-dimensional dynamic row-action maximum likelihood algorithm; image

matrix, 236 × 236 matrix images; and pixel size, 0.78 × 0.78 mm.

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PET image evaluation and quantification of the maximum single-voxel standardized

uptake value (SUVmax) were performed using Xeleris workstation version 1.1452 (GE

Regions

of

interest

were

delineated

within

the

primary

tumor

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Healthcare).

on

attenuation-corrected FDG-PET images and within the ipsilateral normal breast tissue for the

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background uptake, and the SUVmax was measured. The attenuation correction of DbPET was

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carried out as a homogeneous soft tissue of breast tissue composed of mammary gland and fat.

The tumor-to-normal tissue ratio (TNR) was also calculated. All PET images were read by two

Pathological diagnosis

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specialists: a radiologist and a breast cancer specialist.

Before NAC was implemented, samples of primary tumors were collected via core-needle biopsy

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or through a vacuum-assisted core biopsy system (Mammotome Elite; Devicor Medical Products,

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Cincinnati, OH, USA). The histopathological characteristics, such as histology, nuclear grade,

and hormonal receptors and HER2 status, were evaluated at baseline. The residual primary

tumor after NAC was assessed using surgical specimens, and the pathological response was

classified into complete remission (ypT0), residual intraductal disease (ypTis), and residual

invasive disease (ypT≥1).

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Statistical analysis

The summarized data are presented as numbers and percentages unless otherwise stated.

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Frequencies were compared using the Fisher's exact test for categorical variables. The

continuous variables were compared using one-way analysis of variance and the Welch test.

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Receiver operating characteristic curves of the parameters were drawn to determine the cutoff

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value, and the diagnostic capability was predicted by comparing the area under the curve (AUC).

P<0.05 was considered statistically significant. All statistical analyses were performed with EZR

(Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user

Results

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interface for R (The R Foundation for Statistical Computing, Vienna, Austria) [13].

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Forty-five patients (47 tumors) were assessed in this study, and their characteristics are shown in

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Table 1. Twelve tumors developed ypT0, five developed ypTis, and 30 invasive tumors remained.

The median SUVmax from WBPET (WBPET-SUV) was 1.0, whereas that from DbPET

(DbPET-SUV) was 1.9. DbPET-SUV well correlated with WBPET-SUV, and the Pearson

correlation coefficient was 0.892 (95% confidence interval [CI]: 0.813–0.939), as shown in Figure

1.

The associations between the radiologists’ assessment and pathological response are

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shown in Table 2. When pCR was defined as ypT0, DbPET predicted non-pCR more accurately

than WBPET. The sensitivity, specificity, and accuracy of DbPET were 77.1%, 83.3%, and 78.7%,

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respectively, while that of WBPET were 54.3%, 83.3%, and 61.7%, respectively. AUC values for

predicting non-pCR were 0.648 (95% CI: 0.490–0.805) for DbPET and 0.610 (95% CI: 0.448–

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0.771) for WBPET. Conversely, when pCR was defined as ypT0/is, the diagnostic performance

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of DbPET and WBPET was equivalent, and AUCs were 0.653 (95% CI: 0.498–0.808) and 0.641

(95% CI: 0.485–0.798), respectively. DbPET detected all five patients with ypTis, whereas

WBPET detected only one patient with ypTis. Representative images of WBPET and DbPET in

patients who underwent examinations both before and after NAC are shown in Figure 2.

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A comparison of each parameter predicting the treatment response is shown in Figure

3. DbPET-TNR stratified the pathological response better than WBPET-SUV and DbPET-SUV

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(Welch test, P = 0.008, P = 0.134, and P = 0.077, respectively). The AUC of DbPET-TNR for

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predicting ypT0 was 0.807 (95% CI: 0.685–0.930). The cutoffs of WBPET-SUV, DbPET-SUV,

and DbPET-TNR for predicting ypTis and/or ypT≥1 were 1.6, 2.5, and 1.6, respectively.

Discussion

This study demonstrated how DbPET has a higher diagnostic capability for predicting residual

primary breast tumor after NAC, particularly residual intraductal disease (ypTis), when compared

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to WBPET. Moreover, TNR might be a more suitable parameter of pathological response than

SUVmax.

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In this study, we considered both ypT0 and ypT0/is as the definition of pCR to describe

the significance of DbPET in detail. Although pCR predicts long-term outcomes, no standardized

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definition for pCR exists. Some studies have included noninvasive cancer residuals in their pCR

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definition[14, 15], whereas others have defined pCR as the complete remission without

invasive/noninvasive breast tumor[16]. The integrated analysis of pCR definition suggested that

ypT0 was related to the most favorable outcome[17]. Therefore, DbPET’s ability to detect

residual noninvasive breast tumor is important.

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Two parameters, namely, SUVmax and TNR, were calculated to evaluate the capability

of DbPET. The results showed that the accuracy of DbPET-SUV over WBPET-SUV was only

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minimal even for predicting ypT0. The main reasons were the relatively low SUVmax (median

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1.9; interquartile range [IQR]: 1.5–2.7) and the variation of background SUV of DbPET (median

1.5; IQR: 1.1–1.8). These factors might be related to tumor cell density, metabolic activity after

NAC, and reactive changes, such as inflammation and sclerosis. TNR, also called

lesion-to-background ratio in PEM, was used as an objective parameter and might overcome the

aforementioned problems[18-20]. In the present study, TNR reflected the pathological response

after NAC more than SUVmax, and the sensitivity, specificity, and accuracy of DbPET-TNR were

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60.0%, 100%, and 70.2%, respectively, when the cutoff was 1.6.

Although DbPET was superior to WBPET in predicting residual breast tumors,

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including ductal carcinoma in situ, exactly predicting ypT0 via WBPET and DbPET was difficult.

One possible cause is a high false-negative rate (61.5% by WBPET and 44.4% by DbPET),

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which is a major limitation of FDG-PET in general[21]. The previous study evaluated the ability of

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WBPET in predicting residual tumors after NAC, and the sensitivity was 57.5% (threshold SUV:

1.5)[22]. In our study, the sensitivity of DBPET was 77.1%, and the difference was caused by

differences in the resolutions of the equipment and the posture during examinations. Breast PET

imaging in the prone position has been reported to be superior to imaging in the supine position,

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owing to reduced breathing motion, releasing compression of the mammary gland, and

separation from the myocardium in the left breast[23]. Although MRI had a high sensitivity

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(97.6%) for residual tumors, the specificity was low (40.0%)[22]. If pCR could be detected more

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accurately by preoperative imaging, then a clinical trial that omits any breast surgeries for

patients with clinical complete response after NAC might be able to be considered.

This study has some limitations. First, the patient cohort was small, which did not allow

for an analysis according to molecular subtypes. Second, DbPET examinations were performed

only before surgery. A previous study investigated the decreasing rate of SUVmax of WBPET

after each treatment course based on pretreatment examination, and the recommended timing

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of WBPET was after two courses of chemotherapy[24]. We also performed DbPET before NAC,

and the degree of change from pretreatment point will be investigated in a future study. Third, the

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timing and scanning time of WBPET and DbPET examinations differed, and the differences,

which were due to the examination protocols and usage of each PET scanner, might influence

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the SUV values. Although the SUV values of WBPET and DbPET were not the same, they were

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strongly correlated as shown in Figure 1. Thus, it is considered that the influence of difference

in imaging timing on the result is small, and it is a clinical advantage that patients can be inspected by single FDG administration. Last, DbPET was not compared with other modalities,

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such as mammography, US, and enhanced MRI.

Conclusions

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DbPET was useful for predicting residual invasive and noninvasive breast tumor after NAC. TNR

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can be a better indicator of pathological response than SUVmax. We are planning to conduct

further studies with a large cohort to investigate the optimal modality and timing of examinations

and the proper use by subtypes for predicting treatment response after NAC.

Acknowledgements

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We thank Kazushi Marukawa and Masatsugu Tsujimura of Chuden Hospital for providing data

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regarding PET examinations.

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Conflict of Interest statement: None of the authors has a conflict of interest.

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Figure legends

Figure 1. Correlation of SUVmax between WBPET and DbPET. Pearson correlation coefficient

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value; WBPET, whole-body positron emission tomography.

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was 0.892. DbPET, dedicated breast positron emission tomography; SUV, standardized uptake

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Figure 2. Representative images of WBPET (upper) and DbPET (lower) before and after NAC

according to pathological response. The tumor that achieved ypT≥1 was detected on both

examinations (A). The ypTis tumor was detected only on DbPET (B), while the ypT0 tumor

showed no significant uptake on both images (C). DbPET, dedicated breast positron emission

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tomography.

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tomography; NAC, neoadjuvant chemotherapy; WBPET, whole-body positron emission

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Figure 3. Comparison of the parameters for predicting pathological response after NAC using

WBPET and DbPET. DbPET, dedicated breast positron emission tomography; IQR, interquartile

range; NAC, neoadjuvant chemotherapy; TNR, tumor-to-normal tissue ratio; WBPET,

whole-body positron emission tomography.

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Table 1. Tumor characteristics Number (n=47) Tumor stage 10

cT2

30

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cT1

cT3

4

cT4

3

Nodal status cN0

19 21

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cN1 cN2

2 5

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cN3 Histology

Invasive carcinoma of no special type

46

Others

1

ER positive HER2 positive

1 2 3 Unknown

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Operation procedure

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Nuclear grade

30 20

3 9 34 1

17

Mastectomy

28

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Breast-conserving surgery

SUVmax, median (IQR) WBPET

1.0 (0.9–1.4)

DbPET

1.9 (1.5–2.7)

Pathological response

Complete remission (ypT0)

12

Residual intraductal disease (ypTis)

5

Residual invasive disease (ypT≥1)

30

DbPET, dedicated breast positron emission tomography; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; IQR, interquartile range; SUV, standardized uptake value; WBPET, whole-body positron emission tomography.

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Table 2. Diagnostic accuracy of WBPET and DbPET for predicting residual primary breast tumor with and without intraductal disease pCR

WBPET_residual

19

2

WBPET_nonresidual

16

10

DbPET_residual

27

2

DbPET_nonresidual

8

10

WBPET_residual

18

3

WBPET_nonresidual

12

14

DbPET_residual

22

7

DbPET_nonresidual

8

Sensitivity

Specificity

Accuracy

(%)

(%)

(%)

54.3

83.3

61.7

77.1

83.3

78.7

0.007

60.0

82.4

68.1

0.059

73.3

58.8

68.1

P



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0.042

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Non-pCR

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<0.001

10

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DbPET, dedicated breast positron emission tomography; pCR, pathological complete response; WBPET, whole-body positron emission tomography.

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