BREAST MRI IN THE PREOPERATIVE ASSESSMENT OF PATIENTS WITH LOCALLY ADVANCED BREAST CANCER
TREATED WITH NEOADJUVANT ENDOCRINE THERAPY: DIAGNOSTIC
ACCURACY AND CLINICAL UTILITY
Joana Reis
© Joana Reis, 2023
Series of dissertations submitted to the Faculty of Medicine, University of Oslo
1
BREAST MRI IN THE PREOPERATIVE ASSESSMENT OF PATIENTS WITH LOCALLY ADVANCED BREAST CANCER
TREATED WITH NEOADJUVANT ENDOCRINE THERAPY: DIAGNOSTIC
ACCURACY AND CLINICAL UTILITY
Dissertation presented for the degree of Philosophiae Doctor (PhD)
Joana Reis, M.D.
Institute of Clinical Medicine University of Oslo (UiO)
And
Division of Diagnostics and Technology (DDT) Department of Diagnostic Imaging
Breast Radiology Section
Akershus University Hospital (AHUS)
Norway
2
To my husband, and to my grandfather, Joao
“Success is not final; failure is not fatal: it is the courage to continue that counts.”
Sir Winston Churchill
3 Table of Contents
Acknowledgements ... 4
Abbreviations... 5
List of papers... 6
Scientific Oral & Posters Presentations National and International ... 7
Scientific summary ... 8
Vitenskapelig sammendrag ... 10
1. Introduction ... 12
1.1 Thesis at a glance ... 12
1.2 Breast cancer ... 13
Locally advanced breast cancer ... 15
Luminal A (HR+/HER2-) ... 16
1.3 Neoadjuvant endocrine therapy... 17
1.4 Breast magnetic resonance imaging (MRI) ... 18
2. Aims of this work ... 25
2.1 General aims ... 25
2.2 Specific aims of the papers ... 25
3. Material and methods ... 26
3.1 Ethical approval ... 26
3.2 Study design ... 26
3.3 Facilities ... 26
3.4 Patients ... 27
3.5 Randomization and subsequent therapy ... 31
3.6 Breast MRI sequences ... 33
3.7 Contrast administration ... 33
3.8 Image analysis ... 34
Image interpretation and processing ... 34
3.9 Statistical analysis ... 37
4. Summary of the papers ... 39
5. Discussion ... 43
5.1 Methodological considerations ... 43
5.1.1 Study design ... 43
5.1.2 Patients ... 45
5.1.3 Overview of imaging modalities and histological assessment ... 46
5.1.4 Statistical limitations ... 47
5.2 Discussion of the main findings ... 48
5.2.1 MRI of the breast ... 48
5.2.2 MRI in axillary lymph node imaging ... 51
5.2.3 General limitations and challenges ... 52
6. Conclusions ... 55
7. Clinical implications and future aspects ... 57
8. Closing remarks... 59
List of Legends... 61
List of tables... 63
Reference list ... 64
Papers I-III... 77
4 Acknowledgements
I am incredibly grateful to the Institute of Clinical Medicine at the University of Oslo and the Department of Diagnostic Imaging at the Akershus University Hospital (AHUS) for supporting this work over the last four years.
I am very proud to have accomplished all this with many amazing people. It has been an extraordinary journey!
First of all, I have had the opportunity and the privilege to know and work with my three supervisors. Thank you so much for having faith in me, for lifting me up when I needed it most, and for helping me to become a stronger and more competent young researcher.
Professor Jonn Terje Geitung has been my main supervisor and introduced me into the great project NEOLETEXE. His endless patience, constructive criticism, constant availability and optimistic encouragement has been fundamental through the work with this thesis. For his advices, contribution in providing funding, for his efforts to ensure my progress, and for his never-ending support during these last years, a huge THANK YOU.
Professor Jürgen Geisler, my co-supervisor and NEOLETEXE project leader, I will be forever grateful.
Thank you for all the years of guidance, knowledge, and precious advices you have bestowed upon me. It was a privilege to work under your leadership.
I would like to demonstrate my gratitude to my co-supervisor, Kjell-Inge Gjesdal, for his advices, his great technical knowledge in MRI and encouragement.
Thank you very much to the Head of Department of Diagnostic Imaging, Nina Rolland Krogh, the Head of Breast Radiology Section, Evy Gran, the formers Head of General Radiology Section and Head of Resident Unit, Hasan Banitalebi and Haseem Ashraf, respectively, for offering me the roles as a resident, Ph.D- student and breast consultant, for providing me my scientific grant, for allowing me to use the department's MRI facilities and for supporting my work the whole way through.
A special thanks to all the co-authors, Daehoon Park, Hossein Schandiz, Jonas C. Lindstrøm, Laurens C.
Reitsma, Manouchehr Seyedzadeh, Marianne Lyngra, Maryam Lahooti, Nazli Bahrami, Owen Thomas, Torill Sauer and Woldegabriel A. Melles, for the feedbacks, and invaluable thoughts to this work.
As part of assembling all that flowed into this project, my sincere thanks for all the support received from the Departments of Pathology, Oncology, and Department of Breast and Endocrine Surgery. I also wish to acknowledge my colleges, both at the Section of General Radiology and the Breast Section at AHUS, as well as the MR- and Breast radiographers, for creating an educational environment. I really appreciate it.
I am also grateful for the Radiology Department at Nordland Hospital, Bodø, for so warmly and friendly introducing me to the world of radiology, and for taking such great care of me, Daniel Keith, Enno Rodegerdts, Hanne Thoresen, Heidi Haande, Heinrich Backmann, Henrik Stievermann, Jan Prytz, Kari V.
Hustad, Nadide M. Stern, Randi Brendberg, Soniya Javid, Trine Skjeflo, Vanja Cengija, and Zoran Rasic.
Of my non-formal supervisor Alice Cabugueira, please accept my deepest thanks. My dear friends, Aida Lunder, Hang T. Tran and Cezary Wyszynski, thank you for being there at every step, teaching me, and supporting me in my ups and downs. For the bedrock of friendship: Ana Laura Pinto, Catarina Madeira, Cátia Carmo, Mariana Guterres, Pedro Correia and Sofia Miranda.
Many thanks to my cousin, Erica, for talks, advices, dinners and coffees, and for being there. Another thank you to my sister, Mariana, for being so good and so honest, a fierce advocate for my well-being. Enormous thanks to my parents in law, Helena and José, for their encouragement, their steadfast belief in me, and for taking such great care of us four. I owe so much to my parents, Ana and João. Thank you very much for your hard work, sacrifices and for cutting a path so that it might be easier for me to walk. Thank you to my brother, João André, for walking with me. I have had the extraordinarily good fortune of having my grandfather, Joao, who made me feel, since I was just a child, that my dream of becoming a doctor was not only possible, but a foregone conclusion. I cannot repeat thank you enough for that love and admiration, but I will continue to try.
Thank you to my husband, João, best reader and dearest heart, who brought to each reading of these three articles and dissertation all of the intelligence, goodness, patience, and love that he brings to my days. This work and I are better for it.
Most urgently, thank you to Matilde and Henrique, my children, of all that I could achieve in my life, I am most honor and proud to be your “mamma”.
Finally, I wish to acknowledge all patients diagnosed with breast cancer. All of you took on a road you did not ask for and had to accept it. True inspiration!
5 Abbreviations
3D 3 dimensional
ACR American College of Radiology
ADC Apparent diffusion coefficient
AHUS Akershus University Hospital
AI Artificial intelligence
AJCC American Joint Committee on Cancer
ALND Axillary lymph node dissection
ANOVA Analysis of variances
B&A Bland- Altman
BCE Before the Common Era
BCS Breast-conserving surgery
BI-RADS® Breast Imaging- Reporting and Data System
CI Confidence interval
CT Computed tomography
DBT Digital breast tomosynthesis
DCE Dynamic contrast enhanced
DCIS Ductal carcinoma in situ
DSC Dynamic susceptibility contrast
DWI Diffusion-weighted imaging
EES Extravascular extracellular space
EPI Echo planar imaging
ER Estrogen receptor
HER2 Human epidermal growth factor receptor 2
HR Hormone receptor
LABC Locally advanced breast cancer
LN Lymph node
mp Multiparametric
MRI Magnetic resonance imaging
NAC Neoadjuvant chemotherapy
NCCN National Comprehensive Cancer Network
NET Neoadjuvant endocrine therapy
NME Non-mass enhancement
pCR Pathological complete response
PET Positron emission tomography
PR Progesterone receptor
q.d. Once daily
r Pearson correlation coefficient test
RECIST Response Evaluation Criteria in Solid Tumors
rs Spearman's correlation coefficient
SD Standard deviation
SLNB Sentinel lymph node biopsy
SS-EPI Single-shot echo planar imaging
TAD Targeted axillary dissection
T1W T1-weighted
T2W T2-weighted
TFE Turbo field echo
THRIVE T1 weighted high resolution isotropic volume examination
TNM Tumor, node and metastasis
TSE Turbo spin echo
UICC Union for International Cancer Control
US Ultrasound
6 List of papers
Publication # I
Joana Reis, Jonas C. Lindstrøm, Joao Boavida, Kjell-Inge Gjesdal, Daehoon Park, Nazli Bahrami, Manouchehr Seyedzadeh, Woldegabriel A. Melles, Torill Sauer, Jürgen Geisler, Jonn Terje Geitung.
Accuracy of breast MRI in patients receiving neoadjuvant endocrine therapy: comprehensive imaging analysis and correlation with clinical and pathological assessments.
Published in Breast Cancer Research and Treatment 184, 407-420 (2020).
Publication # II
Joana Reis, Owen Thomas, Maryam Lahooti, Marianne Lyngra, Hossein Schandiz, Joao Boavida, Kjell- Inge Gjesdal, Torill Sauer, Jürgen Geisler, Jonn Terje Geitung.
Correlation between MRI morphological response patterns and histopathological tumor regression after neoadjuvant endocrine therapy in locally advanced breast cancer: a randomized phase II trial.
Published in Breast Cancer Research and Treatment 189, 711-723 (2021).
Publication # III
Joana Reis, Joao Boavida, Hang T. Tran, Marianne Lyngra, Laurens Cornelus Reitsma, Hossein Schandiz, Woldegabriel A. Melles, Kjell-Inge Gjesdal, Jürgen Geisler, Jonn Terje Geitung.
Assessment of preoperative axillary nodal disease burden: Breast MRI in locally advanced breast cancer before, during and after neoadjuvant endocrine therapy.
Published in BMC Cancer, 22:702 (2022).
7 Scientific Oral & Posters Presentations National and International
International Poster # I
Joana Reis, Joao Boavida, Kjell-Inge Gjesdal, Nazli Bahrami, Woldegabriel A. Melles, Torill Sauer, Jürgen Geisler, Jonn Terje Geitung.
Accuracy of split dynamic magnetic resonance imaging in locally advanced breast cancer during neoadjuvant aromatase inhibitor therapy.
Presented at SABCS (San Antonio Breast Cancer Symposium) 2019 and published in Cancer Research 80, supplement 4, OT3-02-01 (2020).
Poster # II
Joana Reis, Cathrine H. Kristiansen, Joao Boavida, Jonas C. Lindstrøm, Torill Sauer, Jürgen Geisler, Jonn Terje Geitung.
Dual-layer spectral detector CT: Clinical performance in patients with locally advanced breast cancer treated neoadjuvant with aromatase inhibitors.
Presented at ESMO (European Society for Medical Oncology) 2020 and published in Annals of Oncology 31, supplement 4, S347 (2020).
Poster # III
Joana Reis, Jonas C. Lindstrøm, Joao Boavida, Kjell-Inge Gjesdal, Manouchehr Seyedzadeh, Torill Sauer, Jürgen Geisler, Jonn Terje Geitung.
Accuracy of breast MRI in patients receiving neoadjuvant endocrine therapy: comprehensive imaging analysis and correlation with clinical and pathological assessments.
Presented at ECR (European Society of Radiology) 2021 and published in EPOS, C- 10369 (2021).
Scientific Oral Presentation # I
Joana Reis, Owen Thomas, Maryam Lahooti, Marianne Lyngra, Hossein Schandiz, Joao Boavida, Kjell- Inge Gjesdal, Torill Sauer, Jürgen Geisler, Jonn Terje Geitung.
Correlation between MRI morphological response patterns and histopathological tumor regression after neoadjuvant endocrine therapy in locally advanced breast cancer: a randomized phase II trial.
Presented at ECR (European Society of Radiology) 2022.
National
Scientific Oral Presentation # I
Joana Reis, Joao Boavida, Kjell-Inge Gjesdal, Nazli Bahrami, Woldegabriel A. Melles, Torill Sauer, Jürgen Geisler, Jonn Terje Geitung.
Accuracy of split dynamic magnetic resonance imaging in locally advanced breast cancer during neoadjuvant aromatase inhibitor therapy.
Presented at Radiologisk Høstmøte 2018 (Norway National Congress of Radiology).
Scientific Oral Presentation # II
Joana Reis, Owen Thomas, Maryam Lahooti, Marianne Lyngra, Hossein Schandiz, Joao Boavida, Kjell- Inge Gjesdal, Torill Sauer, Jürgen Geisler, Jonn Terje Geitung.
Correlation between MRI morphological response patterns and histopathological tumor regression after neoadjuvant endocrine therapy in locally advanced breast cancer: a randomized phase II trial.
Presented at Radiologisk Høstmøte 2021 (Norway National Congress of Radiology).
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BREAST MRI IN THE PREOPERATIVE ASSESSMENT OF PATIENTS WITH LOCALLY
ADVANCED BREAST CANCER TREATED WITH NEOADJUVANT ENDOCRINE THERAPY: DIAGNOSTIC ACCURACY AND
CLINICAL UTILITY
Scientific summary
The use of neoadjuvant systemic therapy in the treatment of breast cancer patients is increasing beyond the scope of locally advanced disease.
According to American Joint Committee on Cancer (AJCC) “TNM staging system”, locally advanced disease is classified by stage IIIA- IIIC and a subset of stage IIB cancers (T3N0M0). Otherwise stated, locally advanced disease includes tumors larger than 5 cm with or without regional lymphadenopathy;
tumors of any size with infiltration to the skin and/or to the chest wall, regardless of lymphadenopathy;
and/or presence of advanced regional lymphadenopathy (cN2/cN3; clinically fixed or grouped axillary lymph nodes (LN), or any of supra/infraclavicular, or internal mammary lymphadenopathy) despite of tumor stage.
Neoadjuvant endocrine therapy (NET) is increasingly used in the treatment of locally advanced disease for highly selected patient groups. However, few studies have been conducted with the aim of determining the assessment of treatment response on MRI in patients with locally advanced disease treated with NET.
Imaging provides important information in assessing response to therapy as a complement to conventional tumor measurements via physical examination. MRI allows for improvement of surgical practice, reducing re-excisions while preventing unnecessary mastectomies. Likewise, MRI enables patient selection to neoadjuvant therapies and is the modality of choice for modification of therapeutic agents, for presurgical assessment of residual disease to determine breast-conserving surgery candidacy, and for prediction of pathological complete response (pCR) to triage patients to clinical trials omitting surgery.
The overall aim of this thesis was to discuss and explore the diagnostic feasibility, efficacy and clinical utility of dynamic MRI assessment as an emerging technique for evaluating NET response for patients diagnosed with locally advanced disease.
Paper # I: The main purpose of this paper was to compare tumor size estimated by physical examination and MRI with the tumor size in surgical specimen, in order to determine which is the most accurate assessment to evaluate tumor response in patients with locally advanced disease treated neoadjuvant with aromatase inhibitor therapy.
The correlation between posttreatment MRI size and pathology was higher compared to the correlation between physical examination and pathology. MRI was found to be more accurate for estimating complete responses then clinical assessments. The results of this study provide further support for the benefit of a clinico-imaging preoperative assessment for evaluation of response, residual disease and the importance in deciding patient’s eligibility for breast-conserving surgery.
Paper # II: The main goal of this paper was to determine whether there is a difference in MRI morphological response patterns between pathological responder and non-responder groups during and after completion of locally advanced disease. The secondary goal was to compare the largest tumor diameter of histopathology measurements with the largest tumor diameter obtained from MRI according to MRI morphological response patterns after completion of the intended regimen.
Following 2 and 4 months with therapy, the most common MRI pattern was pattern II (fragmentation).
After 4 months on therapy, the most common histopathological tumor regression grade was grade 3 (moderate partial response to therapy). After 4 months an increasing correlation is observed between MRI patterns and histopathology. The overall correlation, between the largest tumor diameter obtained from MRI and pathology, was moderate and positive (r = 0.50, P-value = 2e-04). Among them, the correlation was highest in type IV (r = 0.53), stable disease.
9 Clearly, prospective evaluation and monitoring of tumor response with breast high-resolution MRI within a clinical trial setting, should routinely incorporate emerging technologies, breast tissue predictive biomarkers, and genetic platforms to allow accurate prediction and assessment of response. Standardized determination of MRI response patterns and histopathological tumor regression models during NET presents promising results and provides valuable information that may help to guide surgeons to choose the best type of surgery for an individual patient. The different MRI response patterns suggest the existence of distinct subgroups of luminal-A patients that deserve additional investigation to improve the use of response evaluations techniques during NET even further.
Paper # III: The aim of this paper was to evaluate the diagnostic reliability of MRI for axillary nodal disease in locally advanced disease patients treated neoadjuvant with endocrine therapy.
Overall, the data presented in this thesis allows for a better understanding and facilitates a comprehensive platform of the current use and the necessary future steps for clinical implementation, pre- and post- therapeutic patient stratification and standardization of MRI of the breast in assessment tumor response to NET in locally advanced disease.
All eligible patients had a target LN reduction, the greatest treatment benefit from week 8 to week 16. There was a positive correlation between the maximal diameter of the most suspicious LN measured by MRI and pathology during and after NET, being highest at therapy completion (r = 0.6, P ≤ .001). Mean and median differences of maximal diameter of the most suspicious LN were higher with MRI than with pathology.
Diffusion-weighted imaging (DWI) was the only axillary node characteristic significant when associated with pathological node status (χ 2 (4) = 8.118, P = .072).
Our findings are worthy of consideration in a larger cohort of patients, as the importance of breast MRI in prediction of axillary response after NET has not been sufficiently investigated. As the trend towards less aggressive axillary surgery continues, a more accurate, yet encompassing role for imaging will be required in staging axillary disease.
Within the past few years, dynamic breast MRI has been established in the field of breast imaging as the most sensitive modality for breast cancer detection and is the most accurate imaging modality for assessment of tumor response to neoadjuvant therapy. Novel MRI parameters, such as dynamic contrast enhanced (DCE)-MRI with kinetic analysis, Multiparametric (mp)MRI (DWI, MR phosphorus spectroscopic imaging), sodium imaging, chemical exchange saturation transfer imaging, blood oxygen level-dependent MRI and hyperpolarized MRI, as well as hybrid imaging with positron emission tomography/MRI and different radiotracers, are being rapidly advanced and translated into clinical imaging.
A paradigm shift, from morphologic to functional imaging in cancer imaging, is forthcoming.
With further dedicated studies in larger patient cohorts, MRI of the breast has the potential to significantly continue to enhance our understanding of tumor biology, and it can be expected that MRI will play a pivotal role in the genomic, radiomics, machine learning and artificial intelligence era of cancer care, offering patients a more precise and targeted diagnostic and treatment approaches, while therapies without effect are avoided in patients with breast cancer.
10
BREAST MRI IN THE PREOPERATIVE ASSESSMENT OF PATIENTS WITH LOCALLY
ADVANCED BREAST CANCER TREATED WITH NEOADJUVANT ENDOCRINE THERAPY: DIAGNOSTIC ACCURACY AND
CLINICAL UTILITY
Vitenskapelig sammendrag
Diagnostisk nøyaktighet ved MR-bryst i preoperativ vurdering av lokalavansert brystkreftpasienter.
I et doktorgradsprosjekt ved Akershus universitetssykehus HF (AHUS) analyseres data fra «NEOLETEXE trial» og fra standard MR-bryst med mål om å forbedre vurderingen av behandlingsrespons hos pasienter med lokalavansert brystkreft behandlet med endokrin neoadjuvant terapi.
Prosjektet har tittelen «Breast MRI in the preoperative assessment of patients with locally advanced breast cancer treated with neoadjuvant endocrine therapy: diagnostic accuracy and clinical utility».
Studien er et behandlingstilbud til brystkreftpasienter med lokalavansert sykdom, det vil si at de fleste inkluderte pasientene er i en ikke-operabel situasjon. Lokalavansert brystkreft omfatter svulster klassifisert som cT3 eller cT4 og/eller brystkreftsykdom med lokalavansert lymfeknutemetastasering (cN2-3), men hvor det ikke er påvist fjernmetastaser.
Det er ingen konsensus om hvilken behandling pasienter med lokalavansert brystkreft på diagnosetidspunktet bør ha. De fleste er enige om at denne pasientgruppen har behov for multimodal terapi, som inkluderer både optimal systemisk behandling, kirurgisk behandling (hvis mulig) og lokoregional strålebehandling.
For pasienter med hormonreseptor-positiv og HER2-negativ brystkreft er det ikke sett høyere responsrater med neoadjuvant kjemoterapi enn med neoadjuvant endokrin terapi. I denne situasjonen er det standard for kvinner med hormonfølsomme svulster å behandle med en aromatasehemmer i noen måneder (ofte 4-6 måneder) dersom behandling med cellegift er ikke ønsket fra pasientens side eller kontraindisert av andre medisinske grunner. Disse medikamentene er såkalte aromatasehemmere og heter letrozol (Femar®) og exemestane (Aromasin®). Begge medikamenter er allerede godkjent og i brukt som standardbehandling i Norge. Vanligvis behandler man bare med et medikament, mens studiegruppe ønsker å gi begge medikamenter etter hverandre. Studien vil gi flere informasjoner om mekanismer som kommer i gang i svulstene under behandlingen som forklarer at noen pasienter har utmerker effekt, mens andre utvikler behandlingsresistens. Neoadjuvant endokrin behandling er således aktuelt for utvalgte pasienter basert på kartlegging av tumorbiologiske egenskaper. Ved manglende tumorskrumpning under slik behandling eller manglende fall i Ki67 (dersom denne undersøkelsen gjentas), bør pasienten enten opereres eller skiftes til annen behandling dersom resttumor er inoperabel.
I denne studien har MR-undersøkelser av brystene vært utført før oppstart av behandlingen (baseline), etter cirka to måneder (interim) og etter cirka fire måneder (preoperativ), i et cross-over-design.
Formålet med prosjektet er å undersøke diagnostisk nøyaktighet ved neoadjuvant behandling ved standard MR-bryst versus klinisk og patologisk evaluering, både i bryst og axillære lymfeknuter for kontroll av behandlingseffekt. I tillegg er MR-morfologiske responsmønstre korrelert med histopatologisk tumorregresjonsgraderingssystem basert på tumorcellularitet.
MR-bildedanning i diagnostikk av brystkreft har vært emne for en omfattende forskningsaktivitet det siste tiåret. Ved bruk av intravenøse gadoliniumbaserte MR-kontrastmidler oppnår man i større kliniske materialer en diagnostisk sensitivitet på cirka 93 % for påvisning av brystkreft. Imidlertid bidrar en lavere spesifisitet til at metodens rolle i klinisk diagnostikk er uavklart (cirka 71%).
Generelt lader maligne svulster opp intravenøst injiserte MR-kontrastmidler raskere og kraftigere enn benigne svulster og normalt kjertelvev. Dette har sammenheng med høyere vaskularitet og økt kapillærpermeabilitet i kreftsvulster sammenliknet med andre typer vev.
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#Paper I: Hensikten med denne artikkelen var å undersøke diagnostisk nøyaktighet ved standard MR bryst versus klinisk og patologisk evaluering. Resultatene viste at preoperativ standard MR bryst overvurdert svulststørrelse i 25.7% og undervurdert i 68.6%. Korrelasjonen mellom MR-størrelse og patologi etter behandling var moderat og høyere (korrelasjonskoeffisient r:0.64), sammenlignet med korrelasjonen mellom klinisk utreding og patologi (korrelasjonskoeffisient r:0.25). MR bryst var mer nøyaktig å estimere patologisk komplett respons enn klinisk vurdering. Resultatene fra denne studien gir økt styrke til fordel for klinisk-avbildning preoperativ vurdering for evaluering av behandlingsrespons, gjenværende tumorvev og viktigheten av å avgjøre pasientens kvalifisering for brystbevarende operasjon.
#Paper II: Formålet med studien var å korrelere MR-morfologiske responsmønstre med histopatologisk tumorregresjonsgraderingssystem basert på tumorcellularitet i lokalavansert brystkreft behandlet neoadjuvant med tredje generasjons aromatasehemmere. Etter 2 og 4 måneder med neoadjuvant endokrin terapi var MR –mønster II («fragmentering») det vanligste. Etter 4 måneder med terapi var histopatologisk tumorregresjonsgrad 3 den vanligste (partiell patologisk respons, moderat tumorrest (10-50%). Etter 4 måneder observeres en økende korrelasjon mellom MR-morfologiske responsmønstre og histopatologi. Det ble observert en moderat og positiv Pearson korrelasjon mellom MR og histopatologisk største diameter (r
= 0.50, P-verdi = 2e-04). Blant dem var korrelasjonen høyest i mønster IV, «stabil» (r=0,53). Type II MR- mønster "fragmentering" var hyppigere i den patologiske gruppen som responderer; og type I («konsentrisk skrumpning» og IV («stabil») i gruppen som ikke responderer. Type II-mønster viste den beste endokrine responsen og en relativt moderat korrelasjon mellom MR og histopatologisk størrelse, mens type IV- mønster indikerte endokrin resistans, men den sterkeste korrelasjonen mellom MR og histopatologi.
#Paper III: Metastatisk aksillær lymfeknute er en av de viktigste prediktorene for «overall recurrence» og overlevelse, og presis vurdering av lymfeknutenes involvering er en avgjørende komponent i aksillær stadieinndeling. Hovedmål var å evaluere diagnostisk nøyaktighet ved standard MR bryst for axillære lymfeknutemetastasering. Det var en positiv korrelasjon mellom den maksimale diameteren på mest suspekt lymfeknute målt på MR og patologi under og etter neoadjuvant terapi, og var høyest ved terapiavslutning (r=0.6, P.001). Syv av 33 pasienter viste normal postbehandling MR lymfeknute status (yrN0). Av disse 7 yrN0, 3 var ypN0, 2 ypN1 og 2 ypN2. Diffusjonsvektet avbildning (DWI) var den eneste aksillære lymfeknuter parameter som var signifikant når assosiert med patologisk nodestatus (2(4) =8.118, P=0.072). Vårt funn er verdt å undersøke på en større gruppe av pasienter. Det er grunn til å tro at utviklingen av nye MR-bildeteknikker og nye behandlingsmetoder kan øke nytten av MR ved brystkreft og lokalavansert lymfeknutemetastasering.
12
1. Introduction
1.1 Thesis at a glance
The value of clinical examination versus breast MRI before, during and after NET
Prospective study.
Higher correlation with breast MRI.
Both breast MRI and clinical examination underestimated the
lesion size.
Breast MRI-based response patterns during
and after NET
Prospective study.
The type II MRI pattern
“fragmentation” was more frequent in the histopathological
responder group, with a relatively moderate correlation
between sizes from MRI and pathology.
Axillary lymph node metastasis detection by
breast MRI before, during and after NET
Prospective Study.
The performance characteristics of MRI were not completely sufficient to preclude surgical
axillary staging.
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1.2 Breast cancer
Breast cancer is the most frequent malignancy in women and is curable in approximately 70-80%
of patients diagnosed with early- stage, non-metastatic disease (1-3). Advanced (metastatic) disease is considered incurable with currently available therapies. The main goals of these therapies are to prolong survival and control symptoms with low treatment- associated toxicity to maintain or improve quality of life (4).
The global incidence of breast cancer has been constantly increasing, and this trend is likely to continue. Breast cancer has now exceeded lung cancer as the leading cause of global cancer incidence in 2020, with an estimated 2.3 million new cases (641.000 cases in 1980; over 1.6 million in 2010), responsible for 11.7% of all cancer cases as illustrated in figure 1 (2, 5).
Incidence varies worldwide, with higher incidence in high-income regions than in low-income regions.
Figure 1: Most common type of cancer mortality by country in 2020 among women. The numbers of countries represented in each ranking group are included in the legend.
Sung et al. A Cancer Journal for Clinicians, 2021, Source: GLOBOCAN 2020. Reprint with permission from John Wiley and Sons and Copyright Clearance Center.
Breast cancer is also the most common cancer among women in Norway with a total of 3424 women diagnosed in 2020 representing more than 20% of all female cancer cases (3, 6-9). The analysis of national data set for recent years indicate a new increase in incidence. This increase may be related to more sensitive diagnostic techniques both within and outside the Norwegian Breast Cancer Screening Program, and combined with women continuing to have imaging controls after age of 70 (9). Breast cancer mortality was almost stable up to the mid 1990s when it began declining. These Norwegian optimistic results most likely reflect a combination of
14 improved treatment and early detection through the Norwegian Breast Cancer Screening Program (6, 9). Nowadays in Norway, 92% of patients with breast cancer survive their cancer for five years or more (5-year relative survival) (9).
Breast cancer is the fifth leading cause of cancer mortality globally, with 685,000 deaths. Among women, it accounts for 1 in 4 cancer cases and for 1 in 6 cancer deaths, ranking first for incidence in the vast majority of countries (159 of 185 countries) and for mortality in 110 countries as shown on figure 2 (2, 4, 5). The projected death rate is predicted escalate to 805,116 deaths per year by 2030, representing a 43% increase in the absolute number of deaths from breast cancer (4).
Figure 2: Most common type of cancer incidence in 2020 in each country among women. The numbers of countries represented in each ranking group are included in the legend.
Sung et al. A Cancer Journal for Clinicians, 2021, Source: GLOBOCAN 2020. Reprint with permission from John Wiley and Sons and Copyright Clearance Center.
The elevated incidence rates in higher human development index countries reflect a longstanding higher prevalence of reproductive and hormonal risk factors (early age at menarche, later age at menopause, fewer births, older first-time parents, less breastfeeding, menopausal hormone therapy, oral contraceptives) and lifestyle risk factors (alcohol consumption, excess body weight, unhealthy diet and/or physical inactivity), as well as increased detection through organized or opportunistic mammographic screening (5).
Results from studies in the United States, Denmark, Ireland, and Scotland using cancer registry data supplemented with tumor marker information have found that increasing incidence is confined to estrogen receptor (ER)-positive cancer, and the rates are falling for ER-negative cancers (1, 10-13). Explanations include the obesity epidemic, given the stronger and more
15 consistent association of excess body weight with ER- positive cancer, and the impact of breast cancer screening programs (targeting women for mammographic screening and those with positive BRCA mutations), which preferentially detects slow-growing ER-positive cancers (2, 4, 5).
The global burden of female breast cancer, measured by incidence, mortality and economic costs, is major and escalating. Over the past decade, emphasis has been placed on diminishing worldwide disparities in access to detection, diagnosis, multimodal therapies as well as individualized treatment, and novel drugs. Additionally, more data is required for various geographic areas to assess resources needed, cost-effectiveness, and humane approaches for detecting, preventing and/or treating breast cancer.
Locally advanced breast cancer
Locally advanced breast cancer (LABC) represents a heterogeneous disease with several etiologies. Some are neglected primary cancers that have slowly progressed to an advanced stage whereas others result from fast growth disease as a result of an aggressive biology. Neglected primary cancers are more common in unscreened, often in women at higher age and are characteristically low to intermediate nuclear grade cancers that are hormone receptor (HR)- positive and human epidermal growth factor receptor 2 (HER2)-negative. In contrast, LABCs diagnosed between screening intervals or shortly after the first sign or symptom of the disease commonly have high-grade and high-proliferative indices. These cancers are commonly estrogen and progesterone receptor (PR)-negative and may have amplification of HER2 (14-16).
Inflammatory breast cancer is the most aggressive subgroup of LABC presenting with rapid disease growth and involvement of the dermal lymphatic vessels by cancer cells. Inflammatory breast cancer has a high propensity for metastatic spread and confers a poor prognosis (2).
According to American Joint Committee on Cancer (AJCC) “TNM staging system”, LABC is classified by stage IIIA- IIIC and a subset of stage IIB cancers (T3N0M0), table 1 (17-19).
Otherwise stated, LABC includes tumors larger than 5 cm with or without regional lymphadenopathy; tumors of any size with infiltration to the skin and/or to the chest wall, regardless of lymphadenopathy; and/or presence of advanced regional lymphadenopathy (cN2/cN3; clinically fixed or grouped axillary lymph nodes (LN), or any of supra/infraclavicular, or internal mammary lymphadenopathy) despite of tumor stage (14, 17-20).
16 Table 1: Primary tumor anatomic staging: clinical and pathological; Clinical anatomic regional lymph node staging; and Distant metastases: anatomic staging.
Hortobagyi et al. American Joint Committee on Cancer. AJCC cancer staging manual, 8th edition, 2017.
Reprint with permission from Springer Nature Customer Service Center (“SNCSC”).
The management of LABC should be multidisciplinary and based on the extent of the disease and tumor biology. Histological confirmation of the tumor type along with molecular subtype is required before starting therapy. LABC still constitutes a great clinical challenge in the treatment of breast cancer, because a great proportion of patients will eventually relapse, regardless multimodality therapy with curative intent (16).
Luminal A (HR+/HER2-)
The St Gallen International Expert Consensus proposed a new intrinsic biological classification system based on the expression of ER, PR, HER2 and Ki-67 (21). The classification system categorizes invasive breast carcinomas into the following distinct molecular subtypes: luminal A (the most prevalent), luminal B (HER2+/-), HER2-enriched, and basal-like (triple negative), and these subtypes are related to the therapeutic selection (21, 22). Luminal breast cancers account for about 60% of all cases and are associated with the best short‐term prognoses and with good responses to hormonal therapy (23, 24) Luminal A-like tumors are HER2‐negative, strongly ER‐
positive, well differentiated and with low proliferation rates (25, 26). Pathological complete response (pCR) seems to have a different impact on patient outcome according to HER2-subtype with the strongest correlation found in HR-negative disease (26).
17 Considering molecular subtype as a main biologic factor as well as applying early response monitoring with accurate imaging modalities, with early re-biopsy in the pre-operative setting, and /or dynamic biomarkers may help to avoid overtreatment, to minimize therapy resistance, and to optimize the available treatment options (22, 27).
1.3 Neoadjuvant endocrine therapy
Endocrine therapy has established itself as an efficacious treatment for selected ER-positive breast cancers, with a reduction in recurrence rates and increased survival rates (28, 29). Neoadjuvant endocrine therapy (NET) has become a useful approach to selected luminal-A-like tumors with strongly HR-positive expression, mainly in postmenopausal or/and elderly women, offering numerous benefits. First, tumor downstaging, thus increasing breast-conserving surgery (BCS) rates and, in some cases reducing axillary dissection. Second, the ability to directly observe therapeutic efficacy enables a better selection and personalization of the treatment, i.e., expedite surgery or switch to neoadjuvant chemotherapy (NAC) in poor responders; as well as the possibility to evaluate any biological or molecular changes that may lead us to explore new biomarkers, whereas there is no measurable disease to follow when systemic therapy is given in the adjuvant setting. Finally, neoadjuvant therapy provides a unique opportunity for validating and accelerating approval of new drugs (30-38).
The NET with ‘third-generation’ aromatase inhibitors (letrozole, anastrozole and exemestane), the standard treatment option for postmenopausal patients with ER-positive breast cancer in all stages of the disease, have been shown to suppress plasma and tissue estradiol levels by >90 % in vivo (36, 37, 39-42). Letrozole and anastrozole belong to a class named nonsteroidal aromatase inhibitors, but exemestane belongs to a different class, called steroidal aromatase-inactivators (37, 43, 44). These two different classes of aromatase inhibitors differ in their mode of actions on the aromatase enzyme. As reported by Cole et al., letrozole and anastrozole bind competitively and reversibly, with regard to the androgen substrate, to the heme-containing active site of the aromatase complex, while exemestane is a mechanism-based inactivator and binds irreversibly to the active site of the enzyme (41, 43, 44). The clinically observed and studied lack of cross resistance between nonsteroidal and steroidal aromatase inhibitors has been described and posted by several clinical trials, giving the principle use of these different drugs options for metastatic breast cancer (33, 36, 45, 46). In spite of continuous research, the mechanisms behind the observed lack of cross resistance are still not completely understood (35, 41). However, a recent publication demonstrated that the different influence of aromatase inhibitors and inactivators on the adipocytokine leptin may play a role (41, 47, 48).
18 Multiple clinical randomized trials have confirmed that ‘third-generation’ aromatase inhibitors are preferred over ER antagonists such as tamoxifen, due to higher clinical and imaging response rates (38, 49, 50). However, NET still remains an underutilized tool for ER-positive breast cancers and is frequently relegated to the treatment of postmenopausal, elderly or otherwise fragile patients who are not suitable for chemotherapy due to their advanced age or comorbidities. A current published meta-analysis including Semiglazov et al. phase II study, GEICAM trial and NEOCENT trial, together with other small studies that compared NAC and NET, found a higher pCR rate with NAC, whereas no significant difference in overall response rate was observed between those two different treatment schemes (29, 51, 52). The majority of clinical trials of NET utilize treatment durations of 3-4-6 months, while maximal response may require more time (up to 12 months). In addition, NET involves less toxicity and better tolerance when compared with NAC, thus constituting a safe and effective option. Nonetheless, tumors respond differently to NET and not all patients respond in a satisfactory way, sometimes even warranting additional NAC. Therefore, an accurate preoperative assessment could predict and measure responses in a reliable fashion allowing to determine the best time point for surgery and proper surgical approach.
Current efforts are focusing on how best to identify patients at risk for late recurrence, how to manage it and the optimal duration of the intended regimen with NET (31, 38, 53-55).
The NEOLETEXE trial utilized an intrapatient cross-over design to analyse the different effects of these drugs in vivo allowing the participants to function as their own controls for selected comparisons, due to the known interpatient variation of hormone-dependence, intratumor mechanisms of adaption and other factors involved in basic tumor biology (41).
1.4 Breast magnetic resonance imaging (MRI)
Over the past years, the introduction of neoadjuvant systemic therapies, advances in surgical techniques, and new imaging modalities for selecting treatment and surgical planning have resulted in dramatic improvements in local recurrence rates and quality of life in patients diagnosed with LABC (19, 30-35, 38, 49, 50, 55-64). National Comprehensive Cancer Network (NCCN) guidelines state that systemic imaging might be regarded for patients with clinical stage IIB with advanced axillary disease, stage III, locally advanced, and inflammatory breast cancer (17, 18, 65). Current methods for evaluating tumor response and residual tumor size to neoadjuvant therapy consist of physical examination and conventional breast imaging with mammography and ultrasound (US) (66-76). Utilization of breast magnetic resonance imaging (MRI) for evaluation of response to neoadjuvant therapy is included as one of the recommended clinical indications by the American College of Radiology (ACR) and European Society of Breast
19 Imaging and is included in the NCCN guidelines as an optional breast imaging modality (65, 70, 77).
Physical measurement of tumor size with calipers is commonly conducted prior to each therapy cycle or monthly if NET is utilized (32, 49, 66-68, 72, 78-84). The accuracy of clinical breast assessment for determining pCR in LABC patients after neoadjuvant hormonal or chemotherapy is 57%, which is inferior to mammography (74%) and US (79%) (32, 49, 66-68, 72, 82-84).
Challenges with physical examination involve the presence of dense fibroglandular tissue and posttherapy fibrosis, which can overestimate the amount of residual disease. Moreover, interval loss of palpability after treatment does not exclude the presence of residual tumor (32, 49, 67, 72, 82, 83).
Conventional breast images, as diagnostic mammography or digital breast tomosynthesis (DBT) and US of the breast and the axilla, are usually performed at baseline for detection and diagnosis prior to the start of neoadjuvant therapy (32, 49, 67, 72, 74, 75, 82-86).
Dynamic MRI of the breast is the most sensitive modality for breast cancer detection and is the most accurate imaging modality for assessment of tumor response following neoadjuvant systemic therapy, as it is difficult for other modalities to distinguish posttreatment fibrosis or postbiopsy change from residual tumor (66, 69, 77, 78, 81, 87-100). According to Croshaw et al., the positive predictive value of breast MRI was 93%, the negative predictive value was 65%, and the overall diagnostic accuracy was 84% comparing breast MRI with physical examination, mammography and US in determining postneoadjuvant pathologic tumor response in operable breast cancer patients (101) (figure 3).
Breast MRI main indications are staging of known cancer, breast cancer screening in women at high risk, and evaluation of response to neoadjuvant systemic therapy (77, 102, 103). As opposed to mammography and US, dynamic MRI is a functional technique that has emerged as the leading technique for tumor characterization, allowing assessment of tumor microenvironment (70, 73, 77, 95, 102-106).
20 Figure 3: HR+/HER2- LABC on the left side. A and B, Diagnostic bilateral mediolateral oblique and craniocaudal views, respectively, show a irregular high-density mass with indistinct margins and associated spread to the skin in the left breast. C, Diagnostic US scan after diagnostic mammography shows a corresponding irregular hypoechoic mass with acoustic shadowing and associated spread to the skin in the left breast. D, Contrast-enhanced T1- weighted THRIVE at late peak enhancement MRI examinations demonstrating response to treatment and residual tumor size. Description of the 3 different time points from left to right: at baseline (pretreatment), interim (after 2 months with NET) and prior to surgery (after 4 months with NET).
Dynamic contrast-based MRI characterizes vascular features, such as the permeability of blood vessels, in a tissue of interest in combination with administration of an exogenous contrast agent that shortens the local T1 time, presiding to a higher signal on T1-weighted (T1W) images (107- 109). The underlying principle is that neoangiogenesis leads to formation of leaky vessels that allow for faster extravasation of contrast agents, thus leading to rapid local enhancement (77, 102, 104-106, 108-110). Common for DCE- and DSC-MRI is the acquisition of serial MR images before (baseline), during, and after the administration of a MR contrast agent. The contrast agent is normally administered as a single bolus intravenous injection, from where it is transported to the heart and further distributed throughout the body. Once it reaches the tumor capillary bed, the applied contrast agent with small molecular weight will leak into the extravascular extracellular space (EES) until concentration in the interstitium balances that of the blood plasma. This distribution process of contrast agent occurs by passive diffusion, controlled by the differences between the contrast agent concentrations across the capillary walls, named Fick’s law. How fast the contrast agent extravasates is determined by the surface area of capillary permeability and the blood flow (104-106). Once the contrast agent concentration in the interstitium balances that of the blood plasma, the net diffusion of contrast agent is reversed given that the contrast agent is excreted by the kidneys, resulting in a reflux of contrast agent into the vasculature. In DCE-MRI, the dominant effect is increased T1 relaxation, enhancing the signal in this T1W MR acquisition.
A B
D
C
21 By measuring the signal change as a function of time, contrast agent concentration gradients are measured as they evolve, and the resulting signal intensity-time curve reflects underlying physiological properties such as capillary permeability, and plasma- and EES volume fractions (111). Despite improvements in the technique of breast MRI, this principle is still the basis of all clinical MRI protocols. However, most MRI protocols nowadays are multiparametric (mp) (112- 115).
With the advent of targeted therapy, the rates of pCR have been markedly higher, up to 50%–
60%, especially for HER2-positive and triple-negative breast cancers (77, 116). Consequently, there is an increasing interest to assess whether the omission of surgery might be viable in patients in whom imaging findings indicate that pCR is achieved (117, 118). MRI has frequently shown high sensitivities of 83%–92% and intermediate specificities of 47%–63% in the prediction of pCR (74, 77, 94, 119). Absence of enhancement in the tumor bed at visual evaluation is the most commonly used imaging criterion for pCR. It has been described that the absence of enhancement on images from delayed phase MRI increases the probability of pCR 28 times when compared with the presence of residual enhancement (100). However, neoadjuvant therapy-induced fibrosis, inflammation, or granulation tissue even without residual cancer might still lead to enhancement at the tumor site, mimicking residual cancer. The ACR Imaging Network (ACRIN) 6657 study concluded that the highest predictive value for anticipating pathologic response after NAC was achieved by using both MRI and clinical measurements of tumor size (74, 77).
Therapy may reduce enhancement in breast lesions, during and after neoadjuvant therapy, thereby evaluation of late phase enhancement is required. To better determine the surgical tumor size after neoadjuvant therapy, it may be beneficial to evaluate delayed phase images (obtained 6 minutes after contrast material administration), as these better shows residual carcinoma in situ components (120). These findings can be explained by the fact that enhancement of residual in situ components after neoadjuvant therapy tends to be delayed as a result of the antiangiogenic effect of therapy (78, 100).
Changes in time–signal intensity curve analysis or pharmacokinetic modeling are also associated with response to NAC, with an early decrease in enhancement as an important predictor of eventual response (121, 122). Likewise, an increase in apparent diffusion coefficient (ADC) is predictive of response, with a reported sensitivity and specificity of 88% and 79% for the prediction of pCR (123, 124).
Treatment response assessment to neoadjuvant therapies, changes in maximum tumor size, tumor volume, and enhancement kinetics at imaging have been continually explored, and functional techniques, including various diffusion-weighted imaging (DWI) approaches and molecular
22 imaging techniques, are being investigated, particularly concerned NAC (70, 77, 102, 112, 120, 125, 126).
The Response Evaluation Criteria in Solid Tumors (RECIST) are the most widely used standardized criteria for response assessment (68). Four categories of response—complete response, partial response, stable disease, and progressive disease- are accepted (79). However, MRI tumor size estimated by using volume measurements are superior to measurements of the longest diameter for predicting therapy response and show a stronger association with recurrence- free survival (71, 89, 95, 127). Several studies have shown that MRI can overestimate or underestimate residual tumor size, with a median correlation coefficient of 0.70 (range, 0.21–0.98) reported in a systematic review by Lobbes et al (128). The potential clinical implication of overestimation of residual tumor size is the resection of a larger amount of tissue during BCS, which may negatively alter cosmetic outcome or influence a decision for mastectomy. The clinical effect of underestimation of residual tumor size is the potential for an incomplete resection with positive surgical resection margins and need for reoperation.
There are two main patterns of tumor size response following neoadjuvant systemic therapy: some tumors can show a concentric shrinkage pattern, while others may fragment into scattered islands of tumor cells embedded in connective and fatty tissue (79, 97, 98, 128). In addition to the effect of NET on tumor size, neoadjuvant systemic therapies often generate a profound effect on tumor cellularity. The overall loss of cellularity after therapy is not always accompanied by a reduction in tumor size, making residual tumor cellularity an important factor in assessing response (79, 129). Kim et al. reported MRI response patterns of breast cancer and concluded that there is a significant difference in MRI- based response patterns following NAC when comparing histopathological responders and non-responders (79, 98).
Tumor molecular subtype is considered a factor that has been shown to affect the diagnostic accuracy of MRI for therapy response assessment. Accuracy of MRI in determining residual tumor size after neoadjuvant therapy is greatest in ER-negative/HER2-positive and triple- negative tumors and is less accurate in HR-positive/HER2-negative tumors in the evaluation of residual tumor and the prediction of pCR (99, 130, 131). The size of lobular or HR- positive/HER2-negative tumors tends to be underestimated. These results can be explained by the fact that HR-positive/HER2-negative tumors more frequently manifest as diffuse non-mass enhancement (NME) and reduce into multiple small foci following neoadjuvant therapy (120, 131). The presence of NME at preoperative MRI is also associated with worse local-regional recurrence-free survival in patients who underwent BCS after NAC, with recurrences usually manifesting in the same quadrant as the original tumor (132). Triple-negative tumors more often
23 manifest as unifocal or multifocal masses than as areas of NME and often show a shrinking reduction pattern after chemotherapy (131).
Metastatic axillary LN is one of the most important predictors of overall recurrence and survival, and precise assessment of LN involvement is a crucial component in axillary staging (133, 134).
While the 5-year survival rate for patients with disease localized to the breast is 98.8%, the figure declines to 85.8% for patients with metastatic regional LN (134). The nodal status often determines the need for systemic therapy, surgical treatment, and radiation therapy (135). Over the past years, the surgical treatment regimen for axillary LN metastases has evolved from routine axillary LN dissection (ALND) toward less extensive procedures, such as the sentinel LN biopsy (SLNB) (133, 136-138). Previous studies have proven SLNB to be a safe technique when cN1 axilla changed to ycN0 after NAC (139-141). Most authors have concluded that NET is less likely to diminish surgery in the axilla than in the breast, even though pCR rates range from 0% to 13.3%
(142, 143). However, SLNB remains associated with morbidity, such as seroma, hematoma, lymphedema, neuropathy, and pain (144). In order to properly address this, a noninvasive axillary nodal staging technique that could substitute SLNB, precisely determine LN-negative breast cancer patients and consequently prevent SLNB associated morbidity should therefore be investigated.
As it has been previously reported in the literature, MRI sensitivity and specificity of axillary imaging are 57-72% and 54-72%, respectively, and accuracy ranging from 60-87% after NAC (136, 145). Alternative noninvasive imaging techniques, such as US or positron emission tomography (PET)- computed tomography (CT), have been used. Although MRI scans do not use ionizing radiation (compared to PET-CT or CT), and exhibit lower intra- and interobserver variability (as in US examinations) (146, 147). Axillary response monitoring during NET could be beneficial to directly observe therapeutic efficacy and proper duration, and to a better selection and personalization of the treatment, i.e., monitoring responders and LN-negative breast cancer patients to a more patient-tailored treatment strategy reducing systemic overtreatment; and in poor- or non-responders to change inefficient treatment, switch to neoadjuvant chemotherapy (NAC) and/or expedite surgery (143, 146-149).
Despite these promising data and inclusion in several clinical practice guidelines, MRI is not presently reliable enough to allow patients to avoid surgery after complete imaging response, and it is not universally used. There are two major limitations. First, long- term patient survival outcomes are not yet known, and it has been speculated that finding small additional tumors at MRI will be unlikely to alter mortality since they might be effectively treated with chemotherapy and/or radiation therapy. Second, there is concern regarding the potential delay in treatment caused by detection of false-positive lesions requiring additional US scan and US or MR imaging-
24 guided biopsy. Patient-specific factors such as inability to tolerate prone positioning, claustrophobia, pacemaker, pregnancy, tattoos and renal impairment are minor limitations.
MRI has an undeniable role in the determination of disease extension, local-regional staging, screening the contralateral breast, and evaluation of tumor response and residual disease after the systemic preoperative treatment.
The current lack of clinical trials and published studies to evaluate the accuracy of breast MRI in predicting pCR and residual disease following NET opens opportunities for evidence-based research. The majority of published studies determines the diagnostic advantages of MRI after NAC. In this context, it is fundamental to understand the different mechanisms of action between chemotherapy and endocrine therapy. Efforts such as these studies will be imperative to guide daily clinical practice, accepting both the available high-level evidence and guidelines to investigate ongoing assessments for evaluating both breast and axilla response to neoadjuvant regimen. The clinical value of our findings is underlined by clinical-radiological-pathological correlation, thus validating the implementation of a standardized grading system, guidelines and imaging monitoring protocols for an accurate and prognostic relevant evaluation of tumor response and residual disease.
25
2. Aims of this work
2.1 General aims
The use of neoadjuvant systemic therapy in the treatment of breast cancer patients is increasing beyond the scope of locally advanced disease. NET is increasingly used in the treatment of LABC for highly selected patient groups. However, few studies have been conducted with the aim of determining the assessment of treatment response on MRI in patients with LABC treated with NET.
Imaging provides important information in determining response to therapy as a complement to conventional tumor measurements via physical examination. MRI improves surgical outcome, reducing re-excisions while preventing unnecessary mastectomies. Likewise, MRI enables patient selection to neoadjuvant therapies and is the modality of choice for modification of therapeutic agents, for presurgical evaluation of residual disease to decide BCS candidacy, and for prediction of pCR to triage patients to ongoing clinical trials omitting breast surgery.
The overall aim of this thesis was to discuss and explore the diagnostic feasibility, efficacy and clinical utility of dynamic MRI assessment as an emerging technique for evaluating NET response for patients diagnosed with LABC (78, 79).
2.2 Specific aims of the papers
Paper # I: Comparison of tumor size calculated by physical examination and MRI with tumor size on pathological evaluation after surgery, in order to analyse which is the most accurate assessment to determine tumor response in LABC patients treated neoadjuvant with aromatase inhibitor therapy.
Paper # II: To examine whether there is a difference in MRI morphological response patterns between pathological responder and non-responder groups during and after NET. The secondary goal was to correlate the largest tumor diameter of pathological measurements with the largest tumor diameter on MRI according to MRI morphological response patterns after completion of the intended regimen.
Paper # III: To evaluate the diagnostic reliability of MRI for axillary nodal disease in LABC patients treated neoadjuvant with endocrine therapy.
26
3. Material and methods
3.1 Ethical approval
NEOLETEXE, a phase 2 clinical trial, was registered on 23/03/2015 in the National trial database of Norway and approved by the Regional Ethical Committee of the South-Eastern Health Region in Norway; registration number: REK-SØ-84-2015.
This substudy of the NEOLETEXE trial was performed in accordance with the Helsinki Declaration, and written informed consent was obtained from all patients prior to participation.
Written informed consent was waived by the Institutional Review Board and the Regional Committee for Medical and Health Research Ethics in the South-East Region of Norway.
3.2 Study design
The NEOLETEXE trial is a neoadjuvant, prospective, randomized, open-label, intrapatient and cross-over single center clinical trial carried out at AHUS, as detailed on figure 4 (41). This thesis is a substudy of the NEOLETEXE trial and to have a homogenous breast cancer population, only LABC patients from this trial were considered eligible. From February 2015, all the participants have been recruited prospectively at the oncological outpatient-clinic at AHUS by local breast cancer oncologists. One hundred and two patients were enrolled. Thereafter, the protocol was closed for further inclusion. The end-of-study was defined as the inclusion of the last participant with all the required data collected according to the protocol procedures.
For all analyses to be conducted, participants were recognized by a code number not allowing personal identification. The manual identification of each patient was recorded on paper, and it was locked in the Department of Oncology and the responsibility of the principal corresponding investigator.
3.3 Facilities
The projects included in this thesis depend on MRI examinations performed only at the Department of Diagnostic Imaging at AHUS. All examinations were conducted on a Philips Ingenia 1.5T system (Philips Healthcare, Best, Netherlands) by using a dedicated 16-channel bilateral breast coil with parallel imaging capabilities with the patient in prone position and both arms elevated with close contact between coil and axillae.
27 Figure 4: Design of the NEOLETEXE trial.
*Time points for breast MRI examinations.
3.4 Patients
Patients with biopsy-proven locally advanced ER-positive and HER2-negative primary cancer suitable for NET were eligible for this protocol. LABC, as aforementioned in the introduction paragraph, is defined as either T3-T4 and/or N2-N3, though patients with tumors larger than 4 cm (but < 5 cm) in diameter have also been includable in accordance with the international trend in clinical trials to extend neoadjuvant therapies in these specific cases (“large T2 tumors”). All participants had to be postmenopausal to benefit from aromatase inhibition with no or very limited distant metastasis. Postmenopausal status was defined as age above 55 years or age above 50 years and at least 2 years of amenorrhea in addition to luteinizing hormone-, follicle-stimulating hormone-, and plasma estradiol levels in the postmenopausal range. The inclusion and exclusion criteria are detailed on table 2.
The detection and diagnosis of breast cancer was established after a mammography or DBT, accompanied by an US of the breast and the axilla, a stereotactic or US- guided breast biopsy and physical examination. Patient selection for neoadjuvant treatment was determined by our multidisciplinary breast cancer team. Primary tumors were classified using clinical and radiological tumor, node and metastasis (TNM) staging system for breast cancer, according to the classification system proposed by the AJCC (2017) and Union for International Cancer Control (UICC, 2017). All patients, as part of their clinical care, were followed at the outpatient-clinic by a medical breast cancer oncologist at least every 4 weeks during the entire study (including caliper measurements in order to determine tumor largest diameter). They were screened for distant metastasis with thoracic, abdominal and pelvic CT scans and bone scintigraphy.
28 Table 2::Inclusion and exclusion criteria.
Routine and study-specific MRI sequences were performed as described below:
• Baseline (before the first treatment regimen).
• Interim (following at least 2 months after the first cycle and prior to crossing-over).
• Preoperative (after the final administration of therapy and immediately before surgery).
Histopathological assessment was evaluated according to the principles within national and international guidelines for standardization of processing and reporting of breast specimens.
Histopathological measurement of residual tumor size, which was used as the gold standard in all the three projects presented in this thesis, was performed in fresh tissue and correlation was tested macro- and microscopically. Microscopic characteristics of the tumor, including histological tumor type and grade, were recorded, along with LN, lymphovascular invasion, and resection margin status. The extent of the tumor was determined applying the standard ypTN (7th edition for papers I and II, and 8th edition for paper III) restaging system of the largest contiguous focus of invasive cancer (T stage) and the extent of regional LN involvement (N stage); yp indicates that patients had received neoadjuvant therapy (16, 20, 129). After the intended regimen with NET all patients underwent BCS or mastectomy, and axillary LNs were surgically removed by SLNB, ALND or both.
Paper # I: Pathological response was defined as complete responder (no residual invasive disease was present) or not complete responder (residual invasive disease present), as illustrated in figure 5. Total extent of residual disease was reported, measured as the greatest one- dimensional extent in centimeters of residual invasive cancer.
Inclusion Criteria Exclusion Criteria
Postmenopausal status Triple-negative breast cancer, HER2+ status ER+/HER-2- Locally advanced breast cancer
(according to AJCC TNM 8thed)
Life-threatening metastasis at diagnosis or during treatment, clinically progressive disease
No or very limited distant metastasis Previous therapy for breast cancer within the last 12 months and/or medications that may interfere with endocrine therapy
Lack of any of the MRIs, lack of sufficient imaging quality
Inconclusive pathological examination Refusal of surgery
29 Figure 5: Panoramic view of histopathological tumor regression grades (hematoxylin-eosin-saffron stain, at 400x magnification) of ER-positive and HER2-negative LABC after 4 months with NET and postsurgery: A, complete pathological response and B, moderate partial response to therapy (10-50% of tumor remaining).
Paper # II: The evaluation of tumor response to treatment was graded based on the recommendations from The Royal College of Pathologists based on neoadjuvant therapy-induced tumor cellularity changes: 1 (complete pathological response), 2 (marked partial response to therapy), 3 (moderate partial response to therapy), 4 (minor partial response to therapy), and 5 (no evidence of response to therapy), (figure 5). Consequently, divided into 2 groups: pathological responder (1, 2 and 3) and non-responder (4 and 5). The details of histopathological tumor regression grading system can be found on table 3. Total extent of residual disease was reported, measured as the greatest one-dimensional extent in centimeters of residual invasive cancer, as in paper I.
Paper # III: Concluding that residual axillary LN metastasis was suspected following physical examination and/or MRI, the patient underwent ALND. For all other patients, SLNB was performed. If no metastasis was found on the frozen sentinel LN, then no further ALND was performed. However, if pathologic examination of the frozen sections for sampled nodes revealed metastases, ALND was performed (116, 150). ypN0 was defined as the complete absence of metastases.
Panel a Panel b
A B
