What Factors Affect Breast Cancer Neoadjuvant Chemotherapy Efficacy?

What Are the Factors Affecting Neoadjuvant Chemotherapy Efficacy in Breast Cancer? A Non-invasive in Vivo Study Using Specialist Magnetic Resonance (MR) Methods

Breast cancer is the most prevalent cancer affecting women. To treat locally advanced breast cancers, neoadjuvant chemotherapy (NACT) is often carried out before surgery to reduce the tumour size to allow breast conservation surgery. However, treatment response for individual patients varies, where the tumour may not respond to treatment and the quality of patient care is compromised if the NACT treatment plan is not optimised. Therefore, the assessment of NACT efficacy is beneficial for the early identification of these patients and appropriate management of treatment.

Breast tumours have unique features compared to healthy tissue, including abnormal tissue structure and biochemical composition. With NACT there are specific changes to such tumour features indicating tumour treatment response.

The purpose of this study is to establish how the changes to breast tumour features following NACT treatment are seen in non-invasive imaging. This study will look at scans of breast tumours using magnetic resonance imaging (MRI). Changes to tissue structure will be measured by advanced diffusion MRI techniques and changes to tumour related biochemical substances will be measured by advanced magnetic resonance spectroscopy techniques. The investigators aim to assess if these techniques can provide information on the tumour treatment response following subsequent rounds of NACT treatment.

In this longitudinal study, 25 patients undergoing NACT will be recruited for four repeated MRI investigations over the course of NACT treatment. Magnetic resonance (MR) measurements of tissue microstructure and biochemical composition will be compared against histological measurements and radiological assessments of treatment response.

The study will recruit patients undergoing treatment at the NHS Grampian. This research is funded by Friends of ANCHOR, Tenovus Scotland Grampian and the NHS Grampian Endowment Research Fund.

Study Overview

• Status: Unknown
• Conditions: Breast Neoplasm Malignant Breast Tissue
• Intervention / Treatment: Other: Magnetic Resonance Imaging; Other: Histopathological Analysis; Other: Health Questionnaire

Detailed Description

In this single group longitudinal study, the investigators propose that functional images from magnetic resonance (MR) methods performed at baseline and after 6 cycles of neoadjuvant chemotherapy (NACT) are in agreement with histological findings from pre-treatment biopsy and post-treatment surgically excised tissue. MR methods will be performed at baseline (pre-treatment) and after the 1st, 3rd and 6th (post-treatment) cycles of NACT treatment. The investigators hypothesise that specific physiological changes detected through MR methods are a manifestation of tumour response to NACT confirmed by histology and radiological assessment (Hypothesis 1). The investigators further hypothesise that early sensitivity to physiological changes manifesting from tumour response to NACT can be revealed by MR measurements after the first and third cycle of treatment (Hypothesis 2).

Research Question 1: Is there a difference in physiological parameters revealed by MR measurements at baseline and after completion of NACT?

Research Question 2: Do the physiological measurements at the completion of NACT from MR measures agree with histological findings?

Research Question 3: Is there a difference between MR measurements at baseline and after the first and third cycle of NACT?

Research Question 4: Is there a difference in MR measurements at baseline, first and third cycle of NACT, between positive treatment responders and non-responders.

MR measurements will be compared against clinical and study specific results from histological analysis and radiological assessment of MRI, mammography and ultrasound measures of tumour treatment response. Information collected from a health questionnaire will supplement interpretation of the data.

To test the effects of NACT on specific aspects of tumour physiology, paired t-tests will be performed on MR measures of lactate concentration, lipid composition and diffusion parameters, between baseline and post-treatment assessments (Research Question 1).

To examine the relationship between MR measurements and histology, correlation analysis will be conducted between baseline and post-treatment assessments. MR measures will be correlated against corresponding percentage changes in histological findings between biopsy and tumour excision (Research Question 2).

To evaluate MR measures as early markers of NACT efficacy, paired t-tests will be carried out between MR measures at pre-treatment and post 1st and 3rd cycles of NACT treatment (Research Question 3), with independent group difference determined between responders and non-responders (Research Question 4).

• Study Type: Interventional
• Enrollment (Anticipated): 25
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Nicholas Senn, MPhys; Phone Number: +44 (0)1224 438351; Email: r03ns15@abdn.ac.uk
• Study Contact Backup: Name: Jiabao He, PhD; Phone Number: +44 (0)1224 437321; Email: jiabao.he@abdn.ac.uk

Study Locations

• United Kingdom
  • Aberdeenshire
    • Aberdeen, Aberdeenshire, United Kingdom, AB25 2ZD
      • Recruiting
      • NHS Grampian
      • Contact: Nicholas Senn, MPhys; Phone Number: +44 (0)1224 43-8351; Email: r03ns15@abdn.ac.uk
      • Principal Investigator: Nicholas Senn, MPhys

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Patients with pathologically confirmed invasive breast cancer undergoing neoadjuvant chemotherapy and surgery.

Exclusion Criteria:

• Condition to contradictive to MRI investigation with contrast agent (poor renal function, contrast agent allergy, metal implants or pace maker).
• Started hormone or chemotherapy treatment before recruitment.
• Undergoing treatment for concurrent cancer diagnosis.
• Marker coil contradictive to MRI investigation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Single Arm; 25 patients with pathologically confirmed invasive breast cancer who will undergo neoadjuvant chemotherapy treatment (NACT) and surgery will be recruited. During the study, patients will receive the standard care and the current study will not alter the care plan offered to them. All patients in the single arm will undergo 4 magnetic resonance imaging scan sessions. Histopathological analysis will be performed on the core biopsy and tumour tissue removed in surgery. Health questionnaire will be completed by each patient.

Other: Magnetic Resonance Imaging; Patients will undergo 4 MRI sessions during NACT treatment. The first scan will take place at treatment baseline before their first cycle of NACT treatment. The second scan will take place following the first treatment cycle prior to the second treatment cycle. Likewise, the third and last scan will take place after the third treatment cycle and sixth (final) treatment cycle prior to surgery. MRI scan sessions will be composed of research scans including diffusion and lipid profiling MR imaging methods and MR spectroscopy (MRS) methods.; Other: Histopathological Analysis; Study specific analysis will be performed on the core biopsy and tissue removed in surgery following the completion of NACT treatment. Standard routine histological analysis will be performed, as well as study specific analysis for immunostaining, grading and slide scan imaging for measurement of cellularity markers.; Other: Health Questionnaire; Health and demographic information will be collected.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline: Water diffusion probability density function (Full-Width-At-Half-Maximum, FWHM, units of micrometre)	The water diffusion probability density function will be quantified by the Full-Width-At-Half-Maximum with units of micrometre	Scan at pre-treatment baseline (Prior to start of Cycle 1, each cycle is 21 days)
Post Cycle 1: Water diffusion probability density function (Full-Width-At-Half-Maximum, FWHM, units of micrometre)	The water diffusion probability density function will be quantified by the Full-Width-At-Half-Maximum with units of micrometre	Scan at the end of Cycle 1 (Each cycle is 21 days)
Post Cycle 3: Water diffusion probability density function (Full-Width-At-Half-Maximum, FWHM, units of micrometre)	The water diffusion probability density function will be quantified by the Full-Width-At-Half-Maximum with units of micrometre	Scan at the end of Cycle 3 (Each cycle is 21 days)
Post Treatment: Water diffusion probability density function (Full-Width-At-Half-Maximum, FWHM, units of micrometre)	The water diffusion probability density function will be quantified by the Full-Width-At-Half-Maximum with units of micrometre	Scan at the end of Cycle 6 (Each cycle is 21 days)
Baseline: Water diffusivity (units of mm^2 /s)	Water diffusivity with units of mm^2 /s	Scan at pre-treatment baseline (Prior to start of Cycle 1, each cycle is 21 days)
Post Cycle 1: Water diffusivity (units of mm^2 /s)	Water diffusivity with units of mm^2 /s	Scan at the end of Cycle 1 (Each cycle is 21 days)
Post Cycle 3: Water diffusivity (units of mm^2 /s)	Water diffusivity with units of mm^2 /s	Scan at the end of Cycle 3 (Each cycle is 21 days)
Post Treatment: Water diffusivity (units of mm^2 /s)	Water diffusivity with units of mm^2 /s	Scan at the end of Cycle 6 (Each cycle is 21 days)
Baseline: Lactate Concentration (units of mM)	Lactate concentration with units of mM	Scan at pre-treatment baseline (Prior to start of Cycle 1, each cycle is 21 days)
Post Cycle 1: Lactate Concentration (units of mM)	Lactate concentration with units of mM	Scan at the end of Cycle 1 (Each cycle is 21 days)
Post Cycle 3: Lactate Concentration (units of mM)	Lactate concentration with units of mM	Scan at the end of Cycle 3 (Each cycle is 21 days)
Post Treatment: Lactate Concentration (units of mM)	Lactate concentration with units of mM	Scan at the end of Cycle 6 (Each cycle is 21 days)
Baseline: Lipid Peak Volume Ratio (Ratio Units)	Lipid peak volume ratio value with units of ratio	Scan at pre-treatment baseline (Prior to start of Cycle 1, each cycle is 21 days)
Post Cycle 1: Lipid Peak Volume Ratio (Ratio Units)	Lipid peak volume ratio value with units of ratio	Scan at the end of Cycle 1 (Each cycle is 21 days)
Post Cycle 3: Lipid Peak Volume Ratio (Ratio Units)	Lipid peak volume ratio value with units of ratio	Scan at the end of Cycle 3 (Each cycle is 21 days)
Post Treatment: Lipid Peak Volume Ratio (Ratio Units)	Lipid peak volume ratio value with units of ratio	Scan at the end of Cycle 6 (Each cycle is 21 days)
Baseline: Fat Fraction (units of %)	Fat Fraction with units of %	Scan at pre-treatment baseline (Prior to start of Cycle 1, each cycle is 21 days)
Post Cycle 1: Fat Fraction (units of %)	Fat Fraction with units of %	Scan at the end of Cycle 1 (Each cycle is 21 days)
Post Cycle 3: Fat Fraction (units of %)	Fat Fraction with units of %	Scan at the end of Cycle 3 (Each cycle is 21 days)
Post Treatment: Fat Fraction (units of %)	Fat Fraction with units of %	Scan at the end of Cycle 6 (Each cycle is 21 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Core Biopsy Tumour Tissue: Ki-67 Staining Percentage (units of %)	Ki-67 staining percentage with units of %, assessed on core biopsy tissue taken prior to start of treatment cycles.	Pre-treatment baseline biopsy (Taken prior to start of Cycle 1, each cycle is 21 days). Assessed following completion of treatment cycles and the routine reporting of core biopsy and excised tissue samples.
Excised Tumour Tissue: Ki-67 Staining Percentage (units of %)	Ki-67 staining percentage with units of %, assessed on excised tissue taken from surgery following completion of treatment cycles.	Post-treatment surgery excision (Post Cycle 6, each cycle is 21 days). Assessed following the completion of routine pathological reporting of the excised tissue.
Core Biopsy Tumour Tissue: Serotonin Staining Score (arbitrary units)	Serotonin staining score with arbitrary units (multiplication of staining percentage and stain intensity scored 1 - 3), assessed on core biopsy tissue taken prior to start of treatment cycles.	Pre-treatment baseline biopsy (Taken prior to start of Cycle 1, each cycle is 21 days). Assessed following completion of treatment cycles and the routine reporting of core biopsy and excised tissue samples.
Excised Tumour Tissue: Serotonin Staining Score (arbitrary units)	Serotonin staining score with arbitrary units (multiplication of staining percentage and stain intensity scored 1 - 3), assessed on excised tissue taken from surgery following completion of treatment cycles.	Post-treatment surgery excision (Post Cycle 6, each cycle is 21 days). Assessed following the completion of routine pathological reporting of the excised tissue.
Core Biopsy Tumour Tissue: Cellularity (units of %)	Cellularity with units of %, assessed on core biopsy taken prior to start of treatment cycles.	Pre-treatment baseline biopsy (Taken prior to start of Cycle 1, each cycle is 21 days). Assessed following completion of treatment cycles and the routine reporting of core biopsy and excised tissue samples.
Excised Tumour Tissue: Cellularity (units of %)	Cellularity with units of %, assessed on excised tissue taken from surgery following completion of treatment cycles.	Post-treatment surgery excision (Post Cycle 6, each cycle is 21 days). Assessed following the completion of routine pathological reporting of the excised tissue.

Collaborators and Investigators

• Sponsor: University of Aberdeen
• Collaborators: NHS Grampian
• Investigators: Study Chair: Jiabao He, PhD, University of Aberdeen; Principal Investigator: Nicholas Senn, MPhys, University of Aberdeen

Publications and helpful links

General Publications

• Graham LJ, Shupe MP, Schneble EJ, Flynt FL, Clemenshaw MN, Kirkpatrick AD, Gallagher C, Nissan A, Henry L, Stojadinovic A, Peoples GE, Shumway NM. Current approaches and challenges in monitoring treatment responses in breast cancer. J Cancer. 2014 Jan 5;5(1):58-68. doi: 10.7150/jca.7047.
• Naressi A, Couturier C, Castang I, de Beer R, Graveron-Demilly D. Java-based graphical user interface for MRUI, a software package for quantitation of in vivo/medical magnetic resonance spectroscopy signals. Comput Biol Med. 2001 Jul;31(4):269-86. doi: 10.1016/s0010-4825(01)00006-3.
• Lee MC, Newman LA. Management of patients with locally advanced breast cancer. Surg Clin North Am. 2007 Apr;87(2):379-98, ix. doi: 10.1016/j.suc.2007.01.012.
• Luangdilok S, Samarnthai N, Korphaisarn K. Association between Pathological Complete Response and Outcome Following Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer Patients. J Breast Cancer. 2014 Dec;17(4):376-85. doi: 10.4048/jbc.2014.17.4.376. Epub 2014 Dec 26.
• Danishad KK, Sharma U, Sah RG, Seenu V, Parshad R, Jagannathan NR. Assessment of therapeutic response of locally advanced breast cancer (LABC) patients undergoing neoadjuvant chemotherapy (NACT) monitored using sequential magnetic resonance spectroscopic imaging (MRSI). NMR Biomed. 2010 Apr;23(3):233-41. doi: 10.1002/nbm.1436.
• Woodhams R, Kakita S, Hata H, Iwabuchi K, Kuranami M, Gautam S, Hatabu H, Kan S, Mountford C. Identification of residual breast carcinoma following neoadjuvant chemotherapy: diffusion-weighted imaging--comparison with contrast-enhanced MR imaging and pathologic findings. Radiology. 2010 Feb;254(2):357-66. doi: 10.1148/radiol.2542090405.
• Walenta S, Mueller-Klieser WF. Lactate: mirror and motor of tumor malignancy. Semin Radiat Oncol. 2004 Jul;14(3):267-74. doi: 10.1016/j.semradonc.2004.04.004.
• Carmona-Fontaine C, Bucci V, Akkari L, Deforet M, Joyce JA, Xavier JB. Emergence of spatial structure in the tumor microenvironment due to the Warburg effect. Proc Natl Acad Sci U S A. 2013 Nov 26;110(48):19402-7. doi: 10.1073/pnas.1311939110. Epub 2013 Nov 11.
• Bolan PJ, Meisamy S, Baker EH, Lin J, Emory T, Nelson M, Everson LI, Yee D, Garwood M. In vivo quantification of choline compounds in the breast with 1H MR spectroscopy. Magn Reson Med. 2003 Dec;50(6):1134-43. doi: 10.1002/mrm.10654.
• Baik HM, Su MY, Yu H, Mehta R, Nalcioglu O. Quantification of choline-containing compounds in malignant breast tumors by 1H MR spectroscopy using water as an internal reference at 1.5 T. MAGMA. 2006 May;19(2):96-104. doi: 10.1007/s10334-006-0032-4. Epub 2006 May 9.
• He Q, Shkarin P, Hooley RJ, Lannin DR, Weinreb JC, Bossuyt VI. In vivo MR spectroscopic imaging of polyunsaturated fatty acids (PUFA) in healthy and cancerous breast tissues by selective multiple-quantum coherence transfer (Sel-MQC): a preliminary study. Magn Reson Med. 2007 Dec;58(6):1079-85. doi: 10.1002/mrm.21335.
• Yamada I, Hikishima K, Miyasaka N, Tokairin Y, Ito E, Kawano T, Kobayashi D, Eishi Y, Okano H. Esophageal carcinoma: Evaluation with q-space diffusion-weighted MR imaging ex vivo. Magn Reson Med. 2015 Jun;73(6):2262-73. doi: 10.1002/mrm.25334. Epub 2014 Jun 19.

Study record dates

Study Major Dates

• Study Start (Actual): May 2, 2018
• Primary Completion (Anticipated): June 1, 2019
• Study Completion (Anticipated): June 1, 2019

Study Registration Dates

• First Submitted: March 28, 2018
• First Submitted That Met QC Criteria: April 9, 2018
• First Posted (Actual): April 18, 2018

Study Record Updates

• Last Update Posted (Actual): May 3, 2018
• Last Update Submitted That Met QC Criteria: May 2, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: Magnetic Resonance Imaging; Neoadjuvant Chemotherapy
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Site; Breast Diseases; Neoplasms; Breast Neoplasms
• Other Study ID Numbers: 2/108/7; 234794 (Other Identifier: Integrated Research Approval System project ID); 17/LO/1777 (Other Identifier: Research Ethics Committee Reference)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No