Association of Standardized Uptake Values of Primary Breast Cancer on [18F]FDG PET/CT With Immunohistochemistry and Molecular Subtypes : Correlation of SUV of primary BC with molecular subtypes

Nishita Goyal; Periakaruppan Gokulakrishnan; Arunan Murali; Leena Joseph Dennis; Rajeswaran Rangasami; Bhawna Dev

doi:10.32768/abc.2023102175-186

Nishita Goyal ⁽¹⁾, Periakaruppan Gokulakrishnan ⁽²⁾, Arunan Murali ⁽³⁾, Leena Joseph Dennis ⁽⁴⁾, Rajeswaran Rangasami ⁽⁵⁾, Bhawna Dev ⁽⁶⁾

(1) Department of Radio-diagnosis, Sri Ramachandra Institute Of Higher Education & Research, Porur, Chennai, India, India,

(2) Department of radio-diagnosis, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai. India, India,

(3) Department of Radio diagnosis Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, India, India,

(4) Department of Pathology, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, India., India,

(5) Deprtment of Radio-diagnosis Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, India., India,

(6) Department of Radio-diagnosis, Sri Ramachandra Institute of Higher Education & Research, Porur Chennai, India., India

https://doi.org/10.32768/abc.2023102175-186

Issue
Volume 10, Issue 2, May 2023

Submitted
January 17, 2023

Published
March 10, 2023

Keywords:

breast cancer, molecular subtype, 18F-FDG, immunohistochemistry, Positron-Emission Tomography, metastasis

PDF XML

Abstract

Background: The prognostic factors for breast cancer include pretreatment staging, nodal and distant metastasis, hormone receptor status, ki67 index, and molecular subtype. For adequate treatment, [18F]FDG PET/CT is now being used to prognosticate the course and response of treatment in breast cancer patients. Our study aims to find the association between the metabolic activity of primary breast tumors as PET/CT SUV uptake and prognostic factors such as ER/PgR/Her2neu receptor status, molecular subtypes, ki67 labeling index, and nodal/distant metastasis.

Methods: A retrospective observational study at our tertiary care institute included 228 breast cancer patients from March 2017 to April 2021. Pretreatment PET/CT imaging was done. The immunohistochemical analysis was performed on a biopsy/surgical specimen to determine the molecular subtype of breast cancer. Further, statistical analysis was performed to find the association between PET/CT findings with immunohistochemistry and thus, molecular subtypes of breast cancers.

Results: Significantly higher SUV max was seen in tumors with ER-negative (Mean SUVmax-11.6; P-value=0.002), PgR negative (Mean SUVmax-11.1; p value-0.0005), triple-negative receptor status (Mean SUVmax-13.7; P-value=0.004) and high Ki67 index (P-value=<0.01). Further Luminal A (Mean SUV max:6.0±5.5 & Median SUV max:3.9±3.6) and Luminal B (Mean SUV max: 8.9±4.9 & Median SUV max:7.6±4.0) subtypes showed lower SUV max as compared to Her2neu (Mean SUV max: 9.4±5.5 & Median SUV max:8.6±6.2) and TNBC (Mean SUV max: 13.7±12.4 & Median SUV max:10.0±7.6) subtypes. However, only a weak correlation was found for axillary nodal spread p-value – 0.02) and no significant correlation was seen for Her2 receptor status (Mean SUVmax-9.7; p value-0.178) and distant metastasis (P-value=0.26).

Conclusion: The values for different molecular subtypes can be used as Mean SUV or Median SUV uptake. However, owing to data skewing in practical scenarios, we suggest the use of median values with interquartile range for predicting the molecular subtypes of breast cancer on PET/CT imaging: Luminal A – Median SUV – 3.9 (IQR – 3.6); Luminal B – Median SUV – 7.6 (IQR – 4.0); Her2neu Enriched – Median SUV 8.6 (IQR - 6.2); Triple-negative breast cancer - Median SUV 10.0 (IQR - 7.6).

Full text article

Generated from XML file

References

Brock CS, Meikle SR, Price P. Does fluorine-18 fluorodeoxyglucose metabolic imaging of tumors benefit oncology? Eur J Nucl Med. 1997 Jun;24(6):691–705. doi: 10.1007/BF00841411.

Oshida M, Uno K, Suzuki M, Nagashima T, Hashimoto H, Yagata H, et al. Predicting the prognoses of breast carcinoma patients with positron emission tomography using 2-deoxy-2-fluoro[18F]-D-glucose. Cancer. 1998 Jun 1;82(11):2227–34. PMID: 9610703

Mauri FA, Maisonneuve P, Caffo O, Veronese S, Aldovini D, Ferrero S, et al. The prognostic value of estrogen receptor status can be improved by combined evaluation of p53, Bcl2, and PgR expression: an immunohistochemical study on breast carcinoma with long-term follow-up. Int J Oncol. 1999 Dec;15(6):1137–1184. doi: 10.3892/ijo.15.6.1137

Clahsen PC, van de Velde CJ, Duval C, Pallud C, Mandard AM, Delobelle-Deroide A, et al. The utility of mitotic index, estrogen receptor, and Ki-67 measurements in the creation of novel prognostic indices for node-negative breast cancer. Eur J Surg Oncol. 1999 Aug;25(4):356–63. doi: 10.1053/ejso.1999.0657.

Ekmekcioglu O, Aliyev A, Yilmaz S, Arslan E, Kaya R, Kocael P, et al. Correlation of 18F-fluorodeoxyglucose uptake with histopathological prognostic factors in breast carcinoma. Nucl Med Commun. 2013 Nov;34(11):1055–67. DOI: 10.1097/MNM.0b013e3283658369.

Kitajima K, Fukushima K, Miyoshi Y, Nishimura A, Hirota S, Igarashi Y, et al. Association between 18F-FDG uptake and molecular subtype of breast cancer. Eur J Nucl Med Mol Imaging. 2015 Aug;42(9):1371–7. doi: 10.1007/s00259-015-3070-1.

Koolen BB, Vrancken Peeters MJTFD, Wesseling J, Lips EH, Vogel WV, Aukema TS, et al. Association of primary tumor FDG uptake with clinical, histopathological, and molecular characteristics in breast cancer patients scheduled for neoadjuvant chemotherapy. Eur J Nucl Med Mol Imaging. 2012 Dec;39(12):1830–8. doi: 10.1007/s00259-012-2211-z.

Ueda S, Tsuda H, Asakawa H, Shigekawa T, Fukatsu K, Kondo N, et al. Clinicopathological and prognostic relevance of uptake level using 18F-fluorodeoxyglucose positron emission tomography/computed tomography fusion imaging (18F-FDG PET/CT) in primary breast cancer. Jpn J Clin Oncol. 2008 Apr;38(4):250–8. doi: 10.1093/jjco/hyn019.

Abubakar ZA, Akepati NKR, Bikkina P. Correlation of Maximum Standardized Uptake Values in 18F-Fluorodeoxyglucose Positron Emission Tomography-computed Tomography Scan with Immunohistochemistry and Other Prognostic Factors in Breast Cancer. Indian J Nucl Med. 2019 Jan-Mar;34(1):10–13. doi: 10.4103/ijnm.IJNM_94_18.

Groheux D, Giacchetti S, Moretti JL, Porcher R, Espié M, Lehmann-Che J, et al. Correlation of high 18F-FDG uptake to clinical, pathological, and biological prognostic factors in breast cancer. Eur J Nucl Med Mol Imaging. 2011 Mar;38(3):426–35. doi: 10.1007/s00259-010-1640-9.

Mavi A, Cermik TF, Urhan M, Puskulcu H, Basu S, Yu JQ, et al. The effects of estrogen, progesterone, and C-erbB-2 receptor states on 18F-FDG uptake of primary breast cancer lesions. J Nucl Med. DOI: 10.2967/jnumed.106.037440.

Osborne JR, Port E, Gonen M, Doane A, Yeung H, Gerald W, et al. 18F-FDG PET of locally invasive breast cancer and association of estrogen receptor status with standardized uptake value: microarray and immunohistochemical analysis. J Nucl Med. 2010 Apr;51(4):543–50. doi: 10.2967/jnumed.108.060459.

Keam B, Im SA, Koh Y, Han SW, Oh DY, Cho N, et al. Early metabolic response using FDG PET/CT and molecular phenotypes of breast cancer treated with neoadjuvant chemotherapy. BMC Cancer. 2011 Oct 20;11(1):452. doi: 10.1186/1471-2407-11-452.

Uğurluer G, Yavuz S, Çalıkuşu Z, Seyrek E, Kibar M, Serin M, et al. Correlation between 18F-FDG Positron-Emission Tomography 18F-FDG Uptake Levels at Diagnosis and Histopathologic and Immunohistochemical Factors in Patients with Breast Cancer. J Breast Health. 2016 Jul 1;12(3):112–8. doi: 10.5152/tjbh.2016.3031.

Dondi F, Albano D, Bellini P, Camoni L, Treglia G, Bertagna F. Relationship between Baseline [18F]FDG PET/CT Semiquantitative Parameters and BRCA Mutational Status and Their Prognostic Role in Patients with Invasive Ductal Breast Carcinoma. Tomogr Ann Arbor Mich. 2022 Oct 27;8(6):2662–75. doi: 10.3390/tomography8060222.

Buck A, Schirrmeister H, Kühn T, Shen C, Kalker T, Kotzerke J, et al. FDG uptake in breast cancer: correlation with biological and clinical prognostic parameters. Eur J Nucl Med Mol Imaging. 2002 Oct;29(10):1317–23. doi: 10.1007/s00259-002-0880-8.

Heudel P, Cimarelli S, Montella A, Bouteille C, Mognetti T. Value of PET-FDG in primary breast cancer based on histopathological and immunohistochemical prognostic factors. Int J Clin Oncol. 2010 Dec;15(6):588–93. doi: 10.1007/s10147-010-0120-3.

Utech CI, Young CS, Winter PF. Prospective evaluation of fluorine-18 fluorodeoxyglucose positron emission tomography in breast cancer for the staging of the axilla related to surgery and immunocytochemistry. Eur J Nucl Med. 1996 Dec;23(12):1588–93. doi: 10.1007/BF01249621.

Koo HR, Park JS, Kang KW, Cho N, Chang JM, Bae MS, et al. 18F-FDG uptake in breast cancer correlates with immunohistochemically defined subtypes. Eur Radiol. 2014 Mar;24(3):610–8. doi: 10.1007/s00330-013-3037-1.

Berriolo-Riedinger A, Touzery C, Riedinger JM, Toubeau M, Coudert B, Arnould L, et al. [18F]FDG-PET predicts complete pathological response of breast cancer to neoadjuvant chemotherapy. Eur J Nucl Med Mol Imaging. 2007 Dec;34(12):1915–24. doi: 10.9738/INTSURG-D-13-00044.1.

Kumar R, Chauhan A, Zhuang H, Chandra P, Schnall M, Alavi A. Clinicopathologic factors associated with false-negative FDG-PET in primary breast cancer. Breast Cancer Res Treat. 2006 Aug;98(3):267–74. doi: 10.1007/s10549-006-9159-2.

Bitencourt AGV, Lima ENP, Chojniak R, Marques EF, de Souza JA, Graziano L, et al. Correlation between PET/CT results and histological and immunohistochemical findings in breast carcinomas. Radiol Bras. 2014;47(2):67–73. doi: 10.1590/S0100-39842014000200006.

Basu S, Chen W, Tchou J, Mavi A, Cermik T, Czerniecki B, et al. Comparison of triple-negative and estrogen receptor-positive/progesterone receptor-positive/HER2-negative breast carcinoma using quantitative fluorine-18 fluorodeoxyglucose/positron emission tomography imaging parameters: a potentially useful method for disease characterization. Cancer. 2008 Mar 1;112(5):995–1000. doi: 10.1002/cncr.23226.

Gianni L, Dafni U, Gelber RD, Azambuja E, Muehlbauer S, Goldhirsch A, et al. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomized controlled trial. Lancet Oncol. 2011 Mar;12(3):236–44. doi: 10.1016/S1470-2045(11)70033-X.

Haffty BG, Yang Q, Reiss M, Kearney T, Higgins SA, Weidhaas J, et al. Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol. 2006 Dec 20;24(36):5652–7. doi: 10.1200/JCO.2006.06.5664.

Shimoda W, Hayashi M, Murakami K, Oyama T, Sunagawa M. The relationship between FDG uptake in PET scans and biological behavior in breast cancer. Breast Cancer Tokyo Jpn. 2007;14(3):260–8. doi: 10.2325/jbcs.14.260.

Prospective multicenter study of axillary nodal staging by positron emission tomography in breast cancer: a report of the staging of breast cancer with PET study group. Womens Oncol Rev. 2004 Jun 1;4(2):151–2. doi: 10.1200/JCO.2004.04.148.

Crippa F, Agresti R, Seregni E, Greco M, Pascali C, Bogni A, et al. Prospective evaluation of fluorine-18-FDG PET in the presurgical staging of the axilla in breast cancer. J Nucl Med. 1998 Jan;39(1):4–8.

Inoue T, Yutani K, Taguchi T, Tamaki Y, Shiba E, Noguchi S. Preoperative evaluation of prognosis in breast cancer patients by [(18)F]2-Deoxy-2-fluoro-D-glucose-positron emission tomography. J Cancer Res Clin Oncol. 2004 May;130(5):273–8. doi: 10.1007/s00432-003-0536-5.

Veronesi U, De Cicco C, Galimberti VE, Fernandez JR, Rotmensz N, Viale G, et al. A comparative study on the value of FDG-PET and sentinel node biopsy to identify occult axillary metastases. Ann Oncol. 2007 Mar;18(3):473–8. doi: 10.1093/annonc/mdl425.

Heusner TA, Kuemmel S, Hahn S, Koeninger A, Otterbach F, Hamami ME, et al. Diagnostic value of full-dose FDG PET/CT for axillary lymph node staging in breast cancer patients. Eur J Nucl Med Mol Imaging. 2009 Oct;36(10):1543–50. doi: 10.1007/s00259-009-1145-6.

Authors

Nishita Goyal

Department of Radio-diagnosis, Sri Ramachandra Institute Of Higher Education & Research, Porur, Chennai, India

https://orcid.org/0000-0001-8236-944X

Periakaruppan Gokulakrishnan

Department of radio-diagnosis, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai. India

https://orcid.org/0000-0001-6370-656X

Arunan Murali

Department of Radio diagnosis Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, India

https://orcid.org/0000-0002-9037-5919

Leena Joseph Dennis

Department of Pathology, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, India.

https://orcid.org/0000-0002-7134-1027

Rajeswaran Rangasami

Deprtment of Radio-diagnosis Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, India.

https://orcid.org/0000-0001-7618-1598

Bhawna Dev

Department of Radio-diagnosis, Sri Ramachandra Institute of Higher Education & Research, Porur Chennai, India.

https://orcid.org/0000-0003-1771-9743

bhawnadev@sriramachandra.edu.in (Primary Contact)

Author Biographies

Nishita Goyal, Department of Radio-diagnosis, Sri Ramachandra Institute Of Higher Education & Research, Porur, Chennai, India

Department of Radio-diagnosis,

Sri Ramachandra Institute Of Higher Education & Research, Porur,

Chennai, India

Periakaruppan Gokulakrishnan, Department of radio-diagnosis, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai. India

Professor,

Department of radio-diagnosis

Sri Ramachandra Institute of Higher Education and Research, Porur,

Chennai.

Arunan Murali, Department of Radio diagnosis Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, India

Professor - Department of Radio diagnosis

Sri Ramachandra Institute of Higher Education and Research, Porur,

Chennai, India

Leena Joseph Dennis, Department of Pathology, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, India.

Professor, Department of Pathology

Sri Ramachandra Institute of Higher Education and Research, Porur,

Chennai, India.

Rajeswaran Rangasami, Deprtment of Radio-diagnosis Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, India.

Professor and Head of the Department,

Deprtment of Radio-diagnosis

Sri Ramachandra Institute of Higher Education and Research, Porur,

Chennai, India.

Bhawna Dev, Department of Radio-diagnosis, Sri Ramachandra Institute of Higher Education & Research, Porur Chennai, India.

Professor, Department of Radio-diagnosis

Sri Ramachandra Institute of Higher Education & Research, Porur

Chennai, India.

Goyal N, Gokulakrishnan P, Murali A, Dennis LJ, Rangasami R, Dev B. Association of Standardized Uptake Values of Primary Breast Cancer on [18F]FDG PET/CT With Immunohistochemistry and Molecular Subtypes : Correlation of SUV of primary BC with molecular subtypes. Arch Breast Cancer [Internet]. 2023 Mar. 10 [cited 2024 Dec. 3];10(2):175-86. Available from: https://archbreastcancer.com/index.php/abc/article/view/668

Download Citation

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Copyright©. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International License, which permits copy and redistribution of the material in any medium or format or adapt, remix, transform, and build upon the material for any purpose, except for commercial purposes.

INTRODUCTION

The prognostic factors for breast cancer include pretreatment staging, nodal and distant metastasis, histopathological type, hormone receptor status, ki67 proliferation index, and molecular subtypes. For adequate treatment, staging and metastatic workup are two important considerations. Histopathological examination (HPE) and immunohistochemistry (IHC) markers are considered the gold standard for diagnosing breast cancer histology and further receptor status. Hormone receptors for breast cancer are the Estrogen receptor (ER), Progesterone receptor (PgR), and Her2neu receptor (Her2), which are further used to characterize molecular subtypes as Luminal A, Luminal B, Her2 Enriched, and Triple negative.

Knowledge of the receptor status and imaging characteristics like size, morphology, and vascularity is vital in guiding the treatment plan. Previously, the use of 18-Fluorodeoxyglucose positron emission tomography / computed tomography ([18F]FDG PET/CT) was limited to pre-treatment, interim, and post-treatment response assessment for cancers. However, the role of PET/CT can be expanded to predict the molecular subtype based on PET/CT uptake values. In the current era, PET/CT is used to prognosticate the affected individuals by correlating it with the HPE and IHC markers. 1 2 This study aims to find the association between metabolic activity of primary tumors as Standardized uptake value (SUV) on PET/CT and prognostic factors such as ER, PgR, and Her2neu receptor status, molecular subtypes, ki67 index, and nodal/distant metastasis. This correlation will help in the management of patients concerning treatment planning, prediction of response, survival, and recurrence rates of breast cancer.

METHODS

Under a waiver of consent by the institutional ethics committee, a retrospective observational study was done at the Department of Radio-diagnosis in our tertiary care institute. The study recruited 228 breast cancer patients from March 2017 to April 2021. The cases under study were either pathologically proven cases of breast cancer who were referred to the radiology department for whole-body PET/CT imaging or were suspicious on imaging for breast cancer and later underwent biopsy/surgical management.

Patients who were undergoing primary breast cancer evaluation with PET/CT (i.e., with no prior treatment for presenting breast complaints) and those with complete IHC panels were included in this study. Patients who obtained any form of treatment before undergoing PET/CT investigation or those without required IHC data were excluded.

All the PET/CT imaging was done using Siemens Biograph Horizon TRUE V PET/CT scanner and Syngo.via version VB30A software. In all the studies, 18F-Fluorodeoxyglucose (dose: 185-555MBq) radiotracer and Iohexol-350mg/dl (dose: 1.5mg/kg) IV contrast agents were used. Post IV contrast administration low dose whole body CT scan with 16 slice CT scanner was performed to acquire slices with 5mm thickness which were reconstructed into 1.5mm thickness slices. Approximately, 1-2 minutes was the routine time to acquire the CT data. PET count acquisition was done in 6 to 7 beds of ~20cm length with exposure time lasting ~2 minutes for each. Detector sensitivity was 7.6cps/kBq at the rate of 435keV with a resolution of 4.2mm. The routine time taken for PET count acquisition was 7-8 minutes. The PET and CT image fusion was done by the software (syngo.via) in the Siemens PET/CT workstation. For measuring the [18F]FDG uptake in a primary lesion, lymph nodes, and distant metastasis, a region of interest (ROI) iso contour was drawn, including the entire lesion. The system calculated and displayed the SUV max of the lesion under consideration. The staging was done according to the AJCC Staging Manual (8th edition).

Histological assessment and interpretation of data were done, and an appropriate block was chosen. Sections of 3µ thickness were cut and immunohistochemical staining was performed using monoclonal antibodies (MAB) at a dilution of 1:100 to the Estrogen Receptor (ER) {rabbit MAB -Alpha (clone EP1) (BioGenex, CA)}, PgR {mouse MAB to PgR (clone PR88) (BioGenex, CA)}, Her2 {rabbit MAB (BioGenex, CA)} and Ki67% {mouse MAB (clone MIB-1) (BioGenex, CA)}. Tumors with >1% nuclear staining were defined as ER and PgR positive (+). Tumors with 2+/3+ positivity were defined as Her2 positive and confirmed by FISH (Fluro in-situ Hybridization). For Ki67%, scoring was done relatively as a percentage of tumor cells positivity with a cut-off of 15%. St. Gallen International Expert Consensus on the primary Therapy of Early Breast Cancer 2011 was used to define the molecular subtypes.

The collected data were analyzed with IBM SPSS Statistics for Windows, Version 23.0 (Armonk, NY: IBM Corp). Descriptive statistics frequency analysis, and percentage analysis were used for categorical variables, and the mean and standard deviation (SD) were used for continuous variables. SUV max differences were calculated by the Kruskal-Wallis test. Spearman's rho was used to Correlate the Ki-67 index and SUV max. Unpaired sample t-test was used to find the significant difference between the bivariate samples in independent groups. For skewed data, the normality of data was verified with Shapiro-Wilk's Test. Median values with interquartile range (IQR) were also calculated for the data. For multivariate analysis, the one-way ANOVA with Tukey's PostHoc test was used. In the above statistical tools, the probability value 0.05 was considered significant.

RESULTS

The mean SUV uptake values were found to be significantly higher for ER/PgR negative and triple negative IHC receptor status. However, no significant association was found for isolated Her2neu receptor status (P-value = 0.17 > 0.05) ( Table 1).

A significant association was found for a higher Ki67 index (>15%) with higher [18F]FDG uptake (P<0.001). (Table 1). The mean SUV max uptake for nodal metastasis was found to be higher in patients with Her2 enriched and TNBC variants compared to the Luminal A and B subtypes (Table 3). On multiple intergroup comparisons of mean SUV max uptake for nodal metastasis, statistical difference was found between Luminal A versus TNBC (P= 0.02). However, no statistical difference was found for Luminal A and Luminal B (P=0.7), Luminal A versus HER2 (P=0.06), Luminal B versus HER2 (P=0.18), and TNBC versus Luminal B (P= 0.07) and HER2 (P= 0.9)

The median SUV max uptake for distant metastasis was almost similar in all the molecular subtypes. On multiple intergroup comparisons of mean distant metastasis SUV max uptake, no statistical difference could be found (P-value-0.26 >0.05) between the various molecular subtypes of breast cancer (Table 3).

DISCUSSION

According to our study, we found that as the [18F]FDG uptake increases in the primary breast lesion, it tends to become more aggressive pathologically. In a study conducted by Brock et al. 1 , it was found that tumors with high [18F]FDG uptake are more aggressive and therefore [18F]FDG uptake on PET/CT scans can be utilized for assessing the prognosis of the disease. According to the study conducted by Oshida et al., 2 the lesions with lower SUV uptake have a better disease-free survival rate, which fits the criteria of a better prognosis of breast cancer.

ER receptor status and [18F]FDG uptake correlation

In studies conducted by Mauri et al. 3 and Clahsen et al. 4 ER positivity status was shown to have a higher disease-free survival rate in the affected patients. In the current study, we found a significant association of ER-negative status with increased [18F]FDG uptake on PET/CT scan (Table. 1) as was also demonstrated in studies conducted by Ekmekcioglu et al. 5 , Kitajima et al. 6 , Koolen et al. 7 , Ueda et al. 8 , Abubakar et al. 9 , Groheux et al. 10 , Mavi et al. 11 , Osborne et al. 12 , Keam et al. 13 , Ugurluer et al. 14 and Dondi et al. 15 (Table 4). However, no significant association between ER-negative status and [18F]FDG uptake was found by Buck et al. 16 , Heudel et al. 17 , and Utech et al. 18 (Table 4).

PgR receptor status and [18F]FDG uptake correlation

The current study found a significant association between PgR negative hormone status with increased [18F]FDG uptake on PET/CT imaging (Table 1) which is in concordance with the results of Ekmekcioglu et al. 5 , Kitajima et al. 6 , Koolen et al. 7 , Abubakar et al. 9 , Groheux et al. 10 , Ugurluer et al. 14 , Dondi et al. 15 and Heudel et al. 17 (Table 4). In comparison to this, studies conducted by Buck et al. 16 (Table 4), Mavi et al. 11 , and Keam et al. 13 did not find a significant association between PgR negative status and SUV max uptake in breast cancer patients.

HER2 gene overexpression and [18F]FDG uptake correlation

Koo et al. 19 stated that HER2-positive breast cancers are characterized by HER2 gene overexpression, which promotes tumor growth and progression. According to the study conducted by Osborne et al.,12 Her2 overexpression is associated with poor prognosis and aggressive disease, which shows comparatively higher uptake of [18F]FDG as compared to ER and PR hormone-positive receptor status. Kitajima et al. 6 (P=0.0002) and Ueda et al. 8 (P=0.006) found a significant association between Her2 overexpression and increased [18F]FDG uptake ( Table 4). As opposed to this, no significant association between the two factors could be determined by our study (Table 1) as well as studies conducted by Ekmekcioglu et al. 5 , Koolen et al. 7 , Abubakar et al. 9 , Mavi et al. 11 , Osborne et al. 12 , Buck et al. 16 , Berriolo-Riedinger et al. 20 , Dondi et al. 15 and Keam et al. 13 (Table 4). Groheux et al. 10 suggested that HER2 has no major role to play in glycolysis, which can be a reason why its overexpression is not significantly associated with higher [18F]FDG uptake.

In a study conducted by Kumar et al. 21 , no significant relationship was found between PET results and tumor type, Her2, and ER/PgR receptors.

PgR receptor status and [18F]FDG uptake correlation

HER2 gene overexpression and [18F]FDG uptake correlation

Luminal subtype and [18F]FDG uptake correlation

In the current study, significant differences were found in [18F]FDG uptake on PET/CT imaging for Luminal type A (Fig.1a,1b and 1c, Fig.2) and Luminal B (Fig.3a, 3b and 3c, Fig.4) molecular subtypes (p<0.001) ( Table 2). These findings were in agreement with the studies conducted by Koolen et al. 7 , Abubakar et al. 9 , and Kitajima et al. 6 Table 5. The comparison between current and previous studies regarding mean/ median SUV uptake values on PET/CT for different molecular subtypes with sample size (n) in each study.

Her2-enriched subtype and [18F]FDG uptake correlation

The Her2-enriched subtype is associated with higher recurrence rates and mortality. The randomized control trial by Gianni et al. 22 concluded that targeted treatment with Trastuzumab monoclonal antibodies has increased the survival rates in such patients. In our study, we found a significantly increased [18F]FDG uptake (P<0.002) in Her2 enriched subtype (Fig. 5a, 5b and 5c, Fig. 6) in comparison to hormone receptor-positive subtypes (Table 2). Similar results (with higher uptake in Her 2 enriched subtype) were demonstrated by Ueda et al. 8 (P <0.001), Bitencourt et al. 23 (P <0.006), Koolen et al. 7 (P <0.0001) and Keam et al. 13 (Table 5). However, the study conducted by Abubakar et al. 9 showed no significant difference in the Her 2 enriched subtype (Table 5). In a study by Kitajima et al. 6 , the Her2 subtype had maximum [18F]FDG uptake (P =0.0002) followed by the triple-negative subtype (P =0.0003) ( Table 5).

Triple-negative breast cancers (TNBC) subtype and [18F]FDG uptake correlation

According to Haffty et al. 25 , TNBC is associated with the most aggressive clinical course and poor prognosis. In our study, we found that the primary pretreated cancers with very high [18F]FDG uptake (Fig. 7a, 7b, and 7c) correlated with TNBC subtypes on immunohistochemistry (Fig. 8) ( Table 2). The findings of our study were supported by studies conducted by Basu et al. 24 , Koolen et al. 7 , Ekmekcioglu et al. 5 , Bitencourt et al. 23 , Groheux et al. 10 and Keam et al. 13 (Table 5). Koolen et al. 7 pointed out that the most beneficial role of PET/CT is in assessing the TNBC since they show high uptake. In a study conducted by Basu et al. 24 , the percentage change in SUV uptake was calculated for TNBC versus non-TNBC, and 100% PET sensitivity was found for TNBC with increased [18F]FDG uptake when compared to the hormone receptor-positive subtypes. Ueda et al. 8 24 suggested, PET/CT can be an important marker for tumor activity and treatment response in breast cancer patients.

Ki67 proliferation index and [18F]FDG uptake correlation

This is a proliferation marker for cancerous cells within the breast parenchyma. As the proliferation index value increases, the grade of carcinoma increases owing to the increased proliferation of malignant cells within the tissue. The cutoff for low and high ki67 has been variable in different studies (e.g., 14 / 15 or 20%) but in our studies, a value <14 % was taken to be a low index and a value ≥14 % as a high index. This marker has invariably shown a positive association with increased [18F]FDG uptake on PET/CT imaging including our study (Table 1) (Fig. 2,4,6 and 8 25 , Abubakar et al. 9 and Keam et al. 13 (Table 4).

Axillary lymph node involvement and [18F]FDG uptake correlation

Lymph node involvement is the prognostic factor with the most variable findings according to previous studies. The study by Heudel et al. 17 found no significant association between morphological and histological characteristics of axillary nodal involvement and the primary subtype of breast cancer (Table 4). However, increased sensitivity and specificity for the detection of nodal involvement were seen on PET/CT. Shimoda et al. 25 determined only a weak correlation between the two factors which corroborates with the findings of the current study (Table 3). According to Wahl et al. 26 , [18F]FDG PET/CT has moderate accuracy for detecting axillary nodal involvement except for small and few axillary nodal metastases. Ekmekcioglu et al. 5 , Abubakar et al. 9 Dondi et al. 15 found a significant association between the high SUV max uptake and nodal enlargement whereas Koolen et al. 7 and Buck et al. 16 found no significant association between the two factors (Table 4). Kumar et al. 21 found no significant relationship between PET results with metastasis for sentinel or distant lymph nodes. Inoue et al. 27 found that the increased [18F]FDG uptake with nodal involvement is a predictor for poor prognosis in breast carcinoma. Veronesi et al. 28 concluded that PET imaging has high specificity, so patients with PET-positive axilla should have an axillary lymph node dissection rather than a sentinel node biopsy for axillary staging similar to the results of the study by Heudel et al. 17 However, due to the low sensitivity of [18F]FDG PET/CT for axillary metastases, PET-negative axillae should undergo sentinel node biopsy, which is also supported by Heusner et al. 29

Distant metastasis and [18F]FDG uptake correlation

Few studies have considered and commented on the correlation between [18F]FDG uptake in distant metastasis involvement along with primary breast cancers. In our study, we found that distant metastasis has no significant association with a higher mean SUV max uptake of the primary breast lesion (P >0.05) ( Table 3). These results are in concordance with the study conducted by Abubakar et al. 9 , in which no significant association was seen between distant metastasis and increased FDG uptake (n = 219, P = 0.086) ( Table 4). A study conducted by Dondi et al. 15 stated that 2 out of 46 cases had distant metastasis on PET/CT imaging with higher SUV max. However, the P -value was 0.2 (insignificant). In contrast, the study conducted by Koolen et al. 7 suggested that metastasis is seen in patients with ER-negative status and higher grades of primary breast cancer (n=214, P <0.006) (Table 4). However, further studies are required to establish a more confident correlation between the two factors.

CONCLUSION

In conclusion, significantly higher SUV max was seen in tumors with ER, PgR negative, triple negative receptor status, and high Ki67 index which is likely to predict poor prognosis in the patient. However, only a weak correlation was found for axillary nodal spread and no significant correlation was seen for distant metastasis.

The values for different molecular subtypes can be calculated and used as Mean or Median SUV uptake. However, owing to data skewing in practical scenarios, we suggest the use of median values (with interquartile range) can be applied for predicting the molecular subtypes of breast cancer on PET/CT Imaging.

Luminal A -Median SUV -3.9 (IQR -3.

CONFLICT OF INTEREST

The authors declare that they have no competing interests.

FUNDING

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

the number of cases taken in the study, ER+ = Estrogen receptor-positive, ER-= Estrogen receptor negative, PgR+ = Progesterone receptor-positive, PgR-= Progesterone receptor negative, HER2+ = Isolated Her2 neu receptor-positive, HER2-= Isolated Her2 neu receptor negative, Non-= Non-Triple negative receptor type, TN or TNBC = Triple negative receptor type, Ki67% = Ki 67 proliferation index, Ab = Number of cases with nodal/ distant metastasis absent, Pr = Number of cases with nodal/ distant metastasis present, P = P-value of significance for each factor calculated and provided by the respective study, Weak/no association = Weak or no association was found between the factors under consideration with P-value > 0.05.

SUV: Mean Standardized Uptake value (maximum) and Median SUV: Median Standardized Uptake value (maximum)

CT(1a), PET(1b), and fusion(1c) images with SUV max uptake of 3.98 in the right breast lesion.

CT(3a), PET(3b), and fusion(3c) images with SUV max uptake of 7.18 in the left breast lesion.

Luminal A Subtype on IHC -(From Upper left to right) (A, B) ER and PgR positive, (C) Her2 -Negative, (D)Ki67 <14%

CT(5a), PET(5b), and fusion(5c) images with SUV max uptake of 9.80 in the right breast lesion.

Luminal B Subtype on IHC -(From Upper left to right) (A, B) ER and PgR positive, (C)Her2 -Negative, (D)Ki67> 14% Association of SUV of primary BC with molecular subtypes Goyal et al. Arch Breast Cancer 2023; Vol. 10, No. 2: 175-186 183 F Figure 7. CT(7a), PET(7b), and fusion(7c) images with SUV max uptake of 13.99 in the left breast lesion.

TNBC -(From Upper left to right) (A, B, C) ER and PgR Her2 -Negative, (D)Ki67 ~80 % Figure 6. Her2neu Enriched Subtype on IHC- From Upper left to right) (A, B) ER and PgR -Negative, (C)Her2 -positive, (D)Ki67 ~ 40%

Luminal B -Median SUV -7.6 (IQR -4.0) Her2neu Enriched -Median SUV 8.6 (IQR -6.2) Triple-negative breast cancer -Median SUV 10.0 (IQR -7.6) ETHICAL CONSIDERATIONS This study was approved by the institutional ethics committee of Sri Ramachandra Institute of Higher Education and Research. Oral consent was obtained from patients and their relatives (IEC number of approval: CSP-MED/17/NOV/40/144).

Read Counter : 871 Download : 27

Share Now

Association of Standardized Uptake Values of Primary Breast Cancer on [18F]FDG PET/CT With Immunohistochemistry and Molecular Subtypes Correlation of SUV of primary BC with molecular subtypes

Abstract

Full text article

References

Authors

Nishita Goyal, Department of Radio-diagnosis, Sri Ramachandra Institute Of Higher Education & Research, Porur, Chennai, India

Periakaruppan Gokulakrishnan, Department of radio-diagnosis, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai. India

Arunan Murali, Department of Radio diagnosis Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, India

Leena Joseph Dennis, Department of Pathology, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, India.

Rajeswaran Rangasami, Deprtment of Radio-diagnosis Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, India.

Bhawna Dev, Department of Radio-diagnosis, Sri Ramachandra Institute of Higher Education & Research, Porur Chennai, India.

Most read articles by the same author(s)

Important Links

Contact Info

Article Sidebar

Abstract

Full text article

References

Authors

Nishita Goyal, Department of Radio-diagnosis, Sri Ramachandra Institute Of Higher Education & Research, Porur, Chennai, India

Periakaruppan Gokulakrishnan, Department of radio-diagnosis, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai. India

Arunan Murali, Department of Radio diagnosis Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, India

Leena Joseph Dennis, Department of Pathology, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, India.

Rajeswaran Rangasami, Deprtment of Radio-diagnosis Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, India.

Bhawna Dev, Department of Radio-diagnosis, Sri Ramachandra Institute of Higher Education & Research, Porur Chennai, India.

Article Details

Most read articles by the same author(s)

Important Links

Contact Info