Exploratory Research on Constructing a Computational Biological Model Based on Next Generation Sequencing Technology for Monitoring Measurable Residual Disease (MRD) After Breast Cancer Surgery
Conditions: Breast Cancer, Measurable Residual Disease
Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University

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SchemeNumber:ZE-OMIX-002
Exploratory Research on Constructing a
Computational Biological Model Based on
Second-generation Sequencing Technology for
Monitoring Measurable Residual Disease
(MRD) after Breast Cancer Surgery
Applicant:
The Second Affiliated Hospital of
Zhejiang University School of Medicine
Team leader unit:
The Second Affiliated Hospital of
Zhejiang University School of Medicine
Main researchers:
Ting Zhang
Versionnumber:
V1.0
Version date:
June 7th, 2023

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Confidentiality Statement
The information contained in this document, especially the unpublished materials, is the property of the
Second Affiliated Hospital of Zhejiang University School of Medicine and is only provided for review
by collaborating researchers, ethics committees, and other relevant collaborating units. Therefore, in
addition to explaining this study to the subjects, written consent from the Second Affiliated Hospital of
Zhejiang University School of Medicine is required before its content can be published.
VersionnumberV1.0
Versiontime:June7,2023
Signature page of the plan
Project name: Exploratory research on constructing a computational biological model based on second-
generation sequencing technology for monitoring minimal residual lesions (MRD) after breast cancer
surgery
Researcher Statement
I have read this plan and the research will be conducted in accordance with the ethical, moral, and
scientific principles outlined in the Helsinki Declaration and the Chinese GCP regulations. I agree to
conduct this clinical study in accordance with the design and regulations of this protocol, and comply
with all the provisions of this protocol.
Researcher(Signature):
Date：
Research Center: Second Affiliated Hospital of Zhejiang University School of Medicine

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Version number V1.0
Version time: June 7, 2023
1.Abstract
project name
Exploratory study on constructing a computational biological model
based on second-generation sequencing technology for monitoring
minimal residual lesions (MRD) after breast cancer surgery
Study type
Prospective, observational, single center clinical studies
indication
Patients diagnosed with primary breast cancer and undergoing
radical breast cancer resection
Plan research cycle
36 months
sample size
80
research objective
Exploring the application value of computational biological model
based on second generation sequencing technology in MRD
monitoring after breast cancer radical surgery；
Research Design and
Planning
This study will include 80 subjects after radical breast cancer
resection, collect blood samples of the above subjects, observe
and quantify the characteristic changes of cfDNA in the blood of
breast cancer subjects after surgery, and establish a computational
biological model based on second-generation sequencing
technology to monitor breast cancer MRD;
Total number of
researchers
80

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Version number V1.0
Version time: June 7, 2023
Inclusion criteria
1. Age ≥18 years old, gender not limited;
2. Obtain plasma samples from the subjects during a 3-
year follow-up period;
3. The subjects fully understand the study and
voluntarily sign the informed consent form; 4. Able to
cooperate with a 3-year follow-up visit to the hospital;
5. The physical fitness status score (ZPS) of the ECOG
scoring criteria for the subjects must be ≤1; 6. Life
expectancy ≥5 years;
7. Subjects who meet the following criteria:
a. Histopathology confirmed primary breast cancer
(unlimited molecular type);
b. Radical breast cancer resection is expected;
c. Adopting postoperative adjuvant therapy or
preoperative neoadjuvant therapy;
Exclusion criteria
1. The subject is pregnant or breastfeeding;
2. Serious mental illness or drug abuse;
3. Unable to obtain the subject's plasma during this
period;
4. If the subject has a non primary malignant tumor of
the breast with a clear pathological diagnosis within 5
years before enrollment:
5. If the subject has suspected non breast malignant
tumors (such as B-ultrasound, CT, etc.) on imaging
within the past year of enrollment, but without
pathological confirmation;
6. Clinical suspicion of distant metastatic lesions;
7. The subject has received any blood product infusion
therapy within the past 30 days; 8. Known carriers of
pathogenic genetic mutations;

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Participate in other interventional clinical studies within
9.3 months;
10. Subjects with poor compliance or deemed unsuitable
by researchers to participate in undergraduate clinical
trials;

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Version number V1.0
Version time: June 7, 2023
Evaluating indicator
Main evaluation indicators:
1. Explore the role of computational biological model
based on second-generation sequencing technology in
monitoring MRD in breast cancer;
2. Disease free survival: The primary endpoint of this
experiment is disease free survival (3 years), which will
be evaluated using RECIST version 1.1;
Secondary evaluation indicators: establish a clinical
cohort of postoperative follow-up for high-risk breast
cancer;
Visit arrangement
screening
period
Visit 1: On the day of subject enrollment
Follow-up
period
Visit 2: One week after adjuvant therapy
Visit 3: 3 months after surgery
Visit 4: 6 months after surgery
Visit 5: 9 months after surgery
Visit 6: 12 months after surgery
Visit 7: 15 months after surgery
Visit 8: 18 months after surgery
Visit 9: 21 months after surgery
Visit 10:24 months after surgery
Visit 11: 30 months after surgery
Visit 12: 36 months after surgery

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Version time: June 7,2023
202023
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2. Research design diagram
Screening criteria for inclusion and exclusion
Sign informed consent form
Collect basic information of subjects
Collect 5ml of peripheral venous blood
and disease progression information from
the subjects at each visit
Multi omics sequencing analysis and
library construction
Establish a computational biological model
Statistical analysis to identify the
application value of the model

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Version time: June 7,2023
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Clinical Trial Process Table
Visits
Project
Screeni
ng
period
Follow-up period
Visits1
Visits2
Visits3
Visits4 Visits5
Visits6 Visits7 Visits8
Visits9
Visits10
Visits11 Visits12
On the
day
of
enro
llme
nt
7 days
after
chem
other
apy
3
mont
hs
after
opera
tion
6
mon
ths
afte
r
oper
atio
n
9
mon
ths
after
oper
atio
n
12
mon
ths
after
oper
atio
15
mon
ths
afte
r
oper
atio
18
mon
ths
after
oper
atio
n
21
mon
ths
after
oper
atio
n
24
month
s after
operat
ion
30
month
s after
operat
ion
36
months
after
opera
tion
Screening criteria
for inclusion and
exclusion
X
Sign informed
consent form
X
Collect basic
information of
subjects
X

Version number V1.0
Version time: June 7,2023
1
Collect disease
development
information from
subjects
X
X
X
X
X
X
X
X
X
X
X
X
Collect 5ml
peripheral venous
blood
X
X
X
X
X
X
X
X
X
X
X
X
AE/SAE records
X
X
X
X
X
X
X
X
X
X
X
X

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3. Research background
3.1 Research Basis
According to the World Health Organization, since 2020, breast cancer has
become the world's largest cancer, accounting for 11.7% of the total incidence rate of
malignant tumors, and ranking first in the number of cases and deaths of female
malignant tumors. According to domestic epidemiological data, the incidence rate of
breast cancer in China is increasing year by year, accounting for 9.1% of the total
number of new cancer cases in China [1], which seriously threatens women's life and
health.
Early breast cancer without distant metastasis is a potentially curable disease [2].
Therefore, early detection, early diagnosis and early treatment have become the focus
of breast cancer diagnosis and treatment. For those patients who have been diagnosed
with breast cancer and need surgical treatment, postoperative recovery and recurrence
monitoring have an important impact on the quality of life and productivity recovery of
patients after surgery. According to relevant research reports, about 94% of breast
cancer patients are in the early stage when they are first diagnosed. However, some of
these early patients still have tumor recurrence after receiving radical treatment, which
is mainly due to the clinical failure to detect minimal residual lesions (MRD) [3].
MRD (Minimum Residual Disease) refers to the small amount of cancer cells
remaining in the body after cancer treatment. The number of residual cancer cells may
be small, causing no signs or symptoms, and cannot be detected by imaging methods,
but they may lead to cancer recurrence. During the process of cell necrosis or apoptosis,
tumor ctDNA is released. At present, second-generation sequencing technology (NGS)
can continuously monitor MRD related cfDNA, which has important guiding
significance for evaluating tumor treatment efficacy, predicting tumor recurrence, and
implementing precise treatment.
Therefore, building a computational biological model that can predict the risk of
tumor recurrence after breast cancer surgery has great medical and social value, and
provides a new clinical idea for postoperative treatment of breast cancer. At present, in
China, scientific research in the field of breast cancer MRD monitoring has not been
carried out on a large scale. Therefore, through the research of this project, we expect
to build a computational biological model combining the second-generation sequencing
technology and computational biology technology to monitor the development of MRD
after breast cancer surgery.
Next Generation Sequencing (NGS) is a collection of high-throughput sequencing
technologies developed in the past two decades. Compared to the first generation
Sanger sequencing method, NGS technology has the ability of multi flux sequencing,
with astonishing improvements in data quality and throughput, and significant cost
reductions [5], thus achieving commercial applications. Although traditional cfDNA
detection techniques have some limitations in terms of sensitivity for postoperative
MRD monitoring, relevant literature suggests that tracking a large number of
individualized tumor mutations in cfDNA can significantly improve the sensitivity of
MRD monitoring, and its sensitivity is positively correlated with the number of
trackable tumor mutations [6]. In this study, we intend to use NGS technology to
monitor the cfDNA of patients with breast cancer after surgery, in order to establish a
database of mutations related to MRD after breast cancer surgery. Computational
biology is an interdisciplinary field that combines biological knowledge and artificial
intelligence to develop and apply methods of data analysis and theory, mathematical
modeling, and computer simulation techniques for the study of biology, behavior, and

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social group systems. With the powerful data processing capabilities of artificial
intelligence machine learning, it has broad application prospects in the field of medical
research involving a large amount of clinical data and bioinformatics data, not limited
to sequencing, but. With the help of computational biology techniques, we can develop
powerful models and even redefine patient categories. In this study, we plan to use
computational biology technology to process the database and build a computational
biological model of MRD monitoring after breast cancer surgery.
At present, globally, tumor early screening products available for monitoring
minimal residual lesions (MRD) mainly include Guardant Reveal from Guardant
Health (USA), Galleri from Grail (USA), and the new liquid biopsy technology
demonstrated by Delfi (USA). These products and technologies have shown great
potential in monitoring postoperative recurrence of malignant tumors.
The cooperating unit of this project, Aomingcheng (Hangzhou) Biotechnology
Co., Ltd., has rich research and development experience in the fields of cancer
genomics and tumor evolution. The company's team has developed a large number of
technical methods for decoding genome functions, which have been widely used in the
Cancer Genome Atlas (TCGA) project. For the first time in the world, they have
discovered a large number of key genes and biological mechanisms that drive the
occurrence and development of various types of cancer, and have mapped the
evolutionary pathways of different tumors. Aomingcheng Company has a globally
leading cancer genomics research platform with a profound and cutting-edge
understanding of tumor evolution. Based on this, innovative medical products can be
developed to improve the existing clinical diagnosis and treatment model of tumors and
fill the huge gap in clinical diagnosis and treatment needs of tumors.
3.2 Risk/Benefit Assessment
3.2.1 Risk Assessment
This study is an observational, prospective clinical study and will not interfere
with the diagnosis and treatment process of patients. Therefore, participating in this
study will not lead to the occurrence of risks such as disease progression in patients.
3.2.2 Benefit assessment
This study is a non intervention observational study, and participation in this study
may not bring direct medical benefits to the subjects. However, the participation of
subjects in this study will help predict the risk of tumor recurrence after radical surgery
for breast cancer, improve the accuracy and sensitivity of tumor recurrence monitoring,
and benefit patients with similar conditions in the future.
4. Research objectives and endpoints
4.1 Main purpose
To establish a computational biological model based on second generation
sequencing technology to monitor MRD, explore the application value of this model in
breast cancer MRD monitoring, and conduct multiple cfDNA multigroup liquid
biopsies in breast cancer patients during postoperative follow-up;
4.2 Secondary Objectives
To establish a clinical cohort for postoperative follow-up of high-risk breast
cancer; It is estimated that 80 patients clinically diagnosed as primary breast cancer
will participate in the screening. After radical resection, blood samples will be
collected for cfDNA multigroup liquid biopsy before radiotherapy. Follow up will be
conducted within 3 years after surgery, including CT/MRI and other imaging tests and
blood tests, and multiple cfDNA multigroup liquid biopsies will be performed
dynamically, and blood samples will be collected 12 times;

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4.3 Study endpoints
Primary endpoint: The number of eligible samples meets the statistical
requirements; Secondary endpoint: The total sample size meets the regulatory
requirements.
5. Research Design
5.1 Overall Design
This clinical trial adopts a prospective, observational, single center trial design,
and selects the Second Affiliated Hospital of Zhejiang University School of Medicine
as the research clinical trial center. After all subjects signed the informed consent form,
they were screened to be qualified, and their basic information was collected for
scientific clinical research to observe the application value of the computational
biological model built based on the second generation gene sequencing for post
operation MRD monitoring of breast cancer.
Single center: This trial provides data support for subsequent statistical analysis,
with a large sample size. Therefore, a single center research-oriented clinical trial is
adopted, which can shorten the time and reduce bias of research-oriented clinical trials.
5.1.1 Screening period (on the day of enrollment)
Participants or their legal representatives must sign a written informed consent
form on a voluntary basis before participating in screening. Only subjects who meet the
inclusion criteria but do not meet the exclusion criteria are eligible to participate in this
experiment. On the day of enrollment, the patients' CA15-3, CEA, color ultrasound and
other traditional postoperative monitoring results of breast cancer were collected, and
5ml of the subjects' peripheral venous blood was collected.
5.1.2 Follow up period (7 days after adjuvant therapy)
After the subjects were screened into the group and received adjuvant treatment 7
days later, they were interviewed 2 to collect the patients' CA15-3, CEA, color
ultrasound and other traditional breast cancer postoperative monitoring results, and
collected 5ml of the subjects' peripheral blood.
5.1.3 Follow up period (3 years after surgery)
After the subjects were screened into the group, they were interviewed for 3-12
months at the 3rd, 6th, 9th, 12th, 15th, 18th, 21st, 24th, 30th, and 36th months after the
operation, to collect the postoperative monitoring results of traditional breast cancer
such as CA15-3, CEA, and color ultrasound, and to collect 5ml of the peripheral blood
of the subjects.
5.2 Encoding Rules
After the subjects are enrolled, they are assigned a subject code in order, starting
with Y07 and followed by the patient's serial number XXX, such as Y07001, Y07002,
Y07003, etc.
After each visit, the blood sample of the subject is given a blood sample code
(single collection of multi tube blood is recorded as the same code), starting with the
subject code of the subject, followed by - DX, where V is the visit and X is the number
of visits in the 12 visits, such as Y07001-V1, Y07003-V7, Y07045-V12, etc. If the
subject's scheduled visit date is postponed from the scheduled date, the total number of
overtime days X (if the visit is scheduled on May 5, 2023 and the subject arrives on
May 8, 2023, then X=3) should be marked after the blood sample code as - XD, such
as Y07001-V2-3D Y07002-V4-2D 、Y07044-V5-12D
Wait.
5.3 Termination of Study
It refers to the clinical study that has not yet been completed according to the
protocol, and all trials are stopped midway. The main purpose of terminating the trial is

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to protect the rights and interests of the subjects, ensure the quality of the trial, and
avoid unnecessary economic losses.
1) Researchers have found significant errors in the clinical protocol during the
trial, making it difficult to evaluate the trial results, or significant deviations in the
implementation of a well-designed protocol, making it difficult to continue evaluating
the trial results;
2) The applicant requests termination (such as funding reasons, management
reasons, etc.);
3) The National Medical Products Administration has ordered the termination of
the trial for some reason.
6. Study population
6.1 Inclusion criteria
1) Age ≥18 years old, gender not limited;
2) Obtain plasma samples from the subjects during a 3-year follow-up period;
3) The subjects fully understand the study and voluntarily sign the informed
consent form;
4) Can cooperate with a 3-year follow-up visit to the hospital;
5) The physical fitness status score (ZPS) of the ECOG scoring criteria for the
subjects must be ≤1;
6) Expected lifespan ≥5 years;
7) Subjects who meet the following criteria:
a. Histopathology confirmed primary breast cancer (unlimited molecular type);
b. Radical breast cancer resection is expected;
c. Adopting postoperative adjuvant therapy or preoperative neoadjuvant therapy;;
6.2 Exclusion criteria
1) The subject is pregnant or breastfeeding;
2) Serious mental illness or drug abuse
3) Unable to obtain plasma from the subject during this period;
4) The subject had a non primary malignant tumor of the breast with a clear
pathological diagnosis within the 5 years prior to enrollment;
5) The subjects have suspected non breast malignant tumors (such as B-ultrasound,
CT, etc.) on imaging within the past year of enrollment, but have not been confirmed
by pathology;
6) Clinical suspicion of distant metastatic lesions;
7) The subject has received any blood product infusion therapy within the past 30
days;
8) Known carriers of pathogenic genetic mutations;
9) Participate in other interventional clinical studies within 3 months;
10) Subjects with poor compliance or deemed unsuitable by researchers to
participate in undergraduate clinical trials;
6.3 Exit criteria
1) The subjects voluntarily withdrew from this study;
2) Participants can choose to withdraw from this study at any time;
6.4 Exclusion criteria
1) Damaged during sample transportation;
2) Subjects who do not meet the inclusion criteria;
3) Subjects who seriously violate the protocol.

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7. Subject withdrawal from the study
7.1 Termination of treatment and withdrawal of subjects from the study
Participants may decide to withdraw from the study at any time, or the researcher
may arrange for participants to withdraw at any time based on safety, behavior,
compliance, and other reasons. But it is expected that this situation is not common.
7.2 Missing Visits
Subjects who have failed to visit the research center for planned visits multiple
times and have not been contacted in a timely manner before the end of the study, thus
unable to confirm their current status through sufficient information, are considered
lost to follow-up.
7.3 Early termination of research
Early termination of a trial refers to the clinical trial not completing the study for
all planned sample sizes according to the protocol, and stopping the entire trial or a part
of the trial (such as a center) midway. The main purpose of early termination is to
protect the rights and interests of the subjects, ensure the quality of the trial, and avoid
unnecessary economic losses.
Under normal circumstances, the experiment will not be terminated prematurely.
But if any of the following situations occur, the entire experiment (or a certain center)
can be terminated in advance
1) The total sample size has met the experimental requirements, but the center has
not completed the enrollment as planned in the contract.
2) The researchers at the center are unable to comply with protocol requirements,
Good Clinical Practice (GCP) for drug/device trials, etc.
3) Obtaining new information leads to unfavorable risk benefit evaluation of the
experimental product, including sufficient evidence indicating a lack of efficacy or
unacceptable safety.
4) Due to medical, ethical, or commercial reasons, the applicant believes that
continuing the clinical trial is inappropriate.
5) The enrollment progress of the subjects is slow and it is impossible to complete
the study within an acceptable time frame.
6) The National Medical Products Administration or Ethics Committee has
ordered the termination of the trial for some reason.
8. Biological samples
8.1 Sample collection and transportation
After the subjects sign the informed consent form, professional nurses will strictly
follow the guidelines during each visit period
Aseptic operation requires 5ml of patient plasma to be collected (using a cfDNA
specific blood collection tube). After blood collection, gently invert 8-10 times, fully
fuse the protective agent, and then place the storage tube upright, indicating the subject
number and visit period number; Collect blood samples and transfer them to a
dedicated blood box.
Professional personnel will seal the transfer box and record the time; Deliver to
the central laboratory of Aomingmingcheng (Hangzhou) Biotechnology Co., Ltd.
within 4-6 hours.
9. Statistical considerations
9.1 Determination of Sample Size
In this study, 80 patients with breast cancer were admitted to the Second Affiliated
Hospital of Zhejiang University School of Medicine.

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9.2 Statistical analysis
The data statistical analysis of this experiment was carried out with the
participation of professional data management and statistical personnel.
10. Adverse Events and Serious Adverse Events
10.1 Definition
10.1.1 Adverse Events
Adverse events (AEs) are defined as any adverse medical events that occur in a
subject and are related in chronological order to drug use, but may not necessarily be
causally related to drug use. Therefore, adverse events may be any adverse, unexpected
symptoms, signs, abnormal test results (such as laboratory test values, ECG) or
diseases (new or aggravated) that are related to the timing of drug use in the study.
10.1.2 Serious Adverse Events
Serious Adverse Event (SAE) refers to any adverse medical event that occurs at
any dose and meets the following description:
●Causing death.
●Endangering life. Note: In the definition of "serious" adverse events, "life-
threatening" refers to the risk of death for the subject at the time of the event. It does
not refer to events that may lead to death in more serious circumstances.
Need for hospitalization or extended hospitalization time.
Note: Generally speaking, hospitalization means that the subject has been left in
the hospital or emergency room (usually for at least one night) for observation and/or
treatment that is not suitable for being conducted in a doctor's office or clinic.
●Causing disability/disability.
Note: The term 'disability' refers to the severe impairment of an individual's ability
to perform daily life functions. This definition does not include events of relatively
minor medical significance, such as headache, nausea, vomiting, diarrhea, influenza,
accidental trauma (such as ankle sprain) and other events without complications that
may interfere with or hinder the function of daily life but without major damage.
Causing congenital abnormalities or birth defects.
Important medical events (which may pose risks to patients or may require
medical/surgical intervention to prevent one of the above outcomes from occurring)
The following are not part of SAE:
Hospitalization for elective treatment due to pre-existing conditions that have not
worsened compared to baseline.
Hospitalization considering social/convenience factors.
·The planned treatment for the target indications of this study includes
hospitalization for infusion therapy or hospitalization due to convenience. 10.2 Record
of Adverse Events
All adverse events should be recorded on the CRF, and the description of the
adverse event should include its start and end time, whether it constitutes a serious
adverse event, measures taken (changes in study treatment, other treatments and related
examinations), and the outcome of the adverse event. The researcher should also
conduct a correlation evaluation.
10.1.3 Grading of Adverse Events
Researchers need to evaluate the severity of each reported AE and SAE during the
study period, and assess and grade adverse events and serious adverse events according
to NCI-CTCAE version 5.0.
Toxicity not applicable to NCI-CTCAE grading will be classified according to the
following definitions:

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·Level 1: Mild; Asymptomatic or mild symptoms; Only clinical or diagnostic
observations have been found; No intervention required
treatment.
·Level 2: Moderate; Requires minimal local or non-invasive intervention therapy;
Equivalent to age
Limited instrumental activities of daily living (ADL).
·Level 3: Severe or medically significant but not directly life-threatening; Need
hospitalization or extension
Length of hospital stay; cause disability; Limited self-care ability in daily life.
Level 4: There are life-threatening consequences; Urgent intervention and
treatment are needed· Level 5: Deaths related to adverse events
10.4 Reporting of Serious Adverse Events
Any serious adverse event must be reported to regulatory authorities and IRB/IEC
within 24 hours of becoming aware, in accordance with applicable regulatory
requirements, by researchers or center personnel. For incomplete reports of serious
adverse events, researchers need to conduct thorough investigations to obtain follow-up
information.
11. Ethical standards
11.1 Informed Consent
Before each patient is enrolled in this study, the research physician has the
responsibility to provide a complete and comprehensive introduction to the purpose
and potential risks of this study. Patients should be informed of their rights, risks, and
benefits. Prior to enrollment, patients should sign an informed consent form and keep it
in the subject folder.
11.2 Ethical norms and policies and regulations
This clinical study must comply with the Helsinki Declaration and relevant
clinical research standards and regulations in China. Before the start of the study, the
protocol must be approved by the ethics committee. Any modifications made to the
research protocol during clinical research should be submitted for ethical review.
Execute according to the approved ethical plan.
12. Quality Assurance
In order to ensure that this study can be conducted strictly in accordance with the
clinical research protocol, clinical researchers should strictly follow the requirements
of the "Investigator Initiated Research Management Measures" throughout the entire
clinical research process, and must ensure standardized research procedures, accurate
research data, and reliable research conclusions.
13. Data processing and data storage
13.1 Case Report Form (CRF)
The case report form should be filled out by the researcher, and the CRF form
should be filled out in a timely manner to ensure accurate content and timely summary.
CRF forms should generally not be altered, and if there are errors that need to be
corrected, a signature and date should be signed at the modification location. 13.2 Data
Preservation
Researchers should keep the data intact. According to the GCP principle in China,
data should be preserved for 10 years after the completion of the research.

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Version number V1.0
Version time: June 7, 2023
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