CN117174338A - Recurrence risk prognosis model for HER2 positive T1N0 breast invasive ductal carcinoma patient - Google Patents
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Abstract
The invention discloses a method and a device for predicting whether a subject, namely a patient with HER2 positive T1N0 breast invasive ductal carcinoma, has poor prognosis, wherein the method comprises the steps of calculating the total score = age score + stage score + ER/PR state score + Ki-67 expression score of the subject, and if the total score is smaller than a cut-off value, indicating that the subject has poor prognosis, and if the total score is larger than the cut-off value, the prognosis is good, wherein the cut-off value is 40.0-50.0 score, and preferably 42.7 score.
Description
Technical Field
The present invention is in the field of cancer prognosis, in particular, prognosis for HER2 positive T1N0 breast invasive ductal cancer patients.
Background
Most prospective phase III clinical trials against HER2 positive early breast cancer have not included T1N0 patients, and thus adjuvant treatment of this population remains controversial. Although the overall prognosis of HER2 positive T1N0 breast cancer patients is good, there are still few patients who experience relapse due to heterogeneity in the population. Furthermore, while studies have shown that chemotherapy in combination with trastuzumab therapy benefits patients on IDFS compared to either pure observations or chemotherapy, absolute benefit is limited. Thus, there is a need in the clinic to build a prognosis model that more finely stratifies this heterogeneous population to guide the physician in more personalized treatment of patients. However, there are few prognostic models for early stage patients with HER2 positivity, and there is a lack of predictive models for early stage patient prognosis. Alex et al scholars established a multivariate prognosis model (HER 2 DX) of early stage HER2 positive breast cancer patients, dividing the patients into low, medium and high risk groups, and guiding the promotion or demotion of systemic adjuvant therapy (Prat A et al A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast cancer: a retrospective study withan external evaluation.the Lancet Oncology 2020; 21:1455-64). However, HER2DX incorporates a large number of non-T1N 0 patients and does not further stratify T1N0 patients according to clinical pathology, thus providing no corresponding assistance in the personalized clinical decision of T1N0 patients.
Disclosure of Invention
To explore the clinical-pathological factors associated with prognosis of this partial population, we conducted a large sample of retrospective real-world studies and long follow-up on HER2 positive T1N0 breast invasive ductal carcinoma patients. Wherein for IDFS the median follow-up time reached 78.0 months. The study found that the confirmed age was less than or equal to 40 years old, stage was T1c, molecular subtype was ER+PR+ and Ki-67 expression levels were independent prognostic risk factors for HER2 positive T1N0 breast invasive ductal carcinoma patients, and based on the above results, the study established a prognostic model for this population for the first time.
The invention can evaluate prognosis of HER2 positive T1N0 breast invasive duct cancer patients, and according to the estimated survival rate calculated by the invention, data reference can be provided for clinicians to implement adjuvant therapy.
In one aspect, the invention directs the clinician whether to apply trastuzumab-targeted therapy during the adjuvant therapy phase: for patients with poor prognosis, the clinician may be prompted to consider adjuvant trastuzumab targeted therapy; for patients with good prognosis, especially patients with good prognosis and risk of targeted therapy, the invention can prompt the clinician to consider avoiding the application of auxiliary trastuzumab targeted therapy so as to avoid excessive therapy, so that the patients can receive less therapy on the premise of not reducing the prognosis of the patients, and the medical risk and economic burden required to be born by the patients are reduced.
On the other hand, as the curative effect of chemotherapy is positively correlated with side effects, the invention can provide a certain realistic data reference for the clinician to select a chemotherapy regimen: for patients with poor prognosis, the invention prompts a clinician to consider selecting a chemotherapy scheme with stronger curative effect; whereas for patients whose invention suggests a good prognosis, the clinician may be prompted to consider selecting a less adverse chemotherapy regimen.
In one aspect, the invention provides a method of predicting whether a subject, i.e., a HER2 positive T1N0 breast invasive ductal carcinoma patient, has a poor prognosis, comprising:
calculating or determining whether the determined age of the subject is greater than or equal to 40 years old or less,
determining a stage of breast cancer in the subject or receiving a stage of breast cancer in the subject, wherein the stage of breast cancer is T1a, T1b, T1c or T1mi,
measuring the ER/PR status of the breast cancer of the subject or receiving the ER/PR status of the breast cancer of the subject, wherein ER/PR status is ER+PR-, ER-PR-, or ER+PR+, respectively,
-measuring the Ki-67 expression level of breast cancer in the subject or receiving whether the Ki-67 expression level of breast cancer in the subject is 30% or more or less, and
-obtaining an age score, a stage score, an ER/PR status score and a Ki-67 expression score based on comparing the above obtained information with the correspondence information shown in fig. 1;
calculate total score = age score + stage score + ER/PR status score + Ki-67 expression score,
if the total score is less than the cutoff value, the prognosis of the subject is indicated as poor, and if the total score is greater than the cutoff value, the prognosis is indicated as good, wherein the cutoff value is 40.0-50.0 points, preferably 42.7 points.
In one aspect, the invention provides an apparatus for predicting whether a subject, i.e., a HER2 positive T1N0 breast invasive ductal carcinoma patient, has a poor prognosis, comprising:
a module for calculating or determining whether the determined age of the subject is greater than or equal to 40 years old or less,
a module for measuring a stage of breast cancer in the subject or receiving a stage of breast cancer in the subject, wherein the stage of breast cancer is T1a, T1b, T1c or T1mi,
a module for measuring the ER/PR status of or receiving the ER/PR status of breast cancer in said subject, wherein ER/PR status is ER+PR-, ER-PR-, ER-PR+ or ER+PR+,
-a module for measuring the expression level of Ki-67 of breast cancer in said subject or for receiving whether the expression level of Ki-67 of breast cancer in said subject is 30% or more, and
-a module for obtaining an age score, a stage score, an ER/PR status score and a Ki-67 expression score based on the comparison of the above obtained information with the correspondence information shown in fig. 1;
a module for calculating a total score = age score + staging score + ER/PR status score + Ki-67 expression score,
a module for displaying the total score of the subject and/or indicating a prognosis prediction result, if the total score is less than a cut-off value, indicating that the subject is not prognosis good, if the total score is greater than a cut-off value, wherein the cut-off value is 40.0-50.0 points, preferably 42.7 points,
-optionally comprising a module that prompts the subject to be recommended to receive adjuvant targeted therapy and/or to receive a more therapeutic chemotherapeutic regimen if the subject has a poor prognosis.
In one aspect, the invention provides a method of treating a HER2 positive T1N0 breast invasive ductal carcinoma subject comprising performing a method of predicting whether a subject, i.e., a HER2 positive T1N0 breast invasive ductal carcinoma patient, is not prognosis-good according to the invention, and if the subject is not prognosis-good, recommending the subject to receive adjuvant targeted therapy and to receive a more therapeutic chemotherapy regimen.
In one aspect, the invention provides an apparatus comprising a digital processor configured to perform the method of predicting whether a subject, i.e., a HER2 positive T1N0 breast invasive ductal carcinoma patient, is prognosis poor and/or the method of treating a HER2 positive T1N0 breast invasive ductal carcinoma subject of the invention.
In one aspect, the invention provides a non-transitory storage medium storing instructions executable by a digital processing device to perform a method of predicting whether a subject, i.e., a HER2 positive T1N0 breast invasive ductal carcinoma patient, is prognosis poor and/or a method of treating a HER2 positive T1N0 breast invasive ductal carcinoma subject as described herein.
In one aspect, the present invention provides a computer program comprising program code means for causing a digital processing device to carry out the method of predicting whether a subject, i.e. a HER2 positive T1N0 breast invasive ductal carcinoma patient, is not prognosis good and/or the method of treating a HER2 positive T1N0 breast invasive ductal carcinoma subject according to the present invention, when the digital processing device runs the computer program.
Drawings
Fig. 1: nomograms of prognostic risk models for IDFS.
Detailed Description
While various embodiments and aspects of the present invention are shown and described herein, those skilled in the art will recognize that such embodiments and aspects are merely illustrative of the invention. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the spirit of the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The techniques and methods described herein are generally performed according to techniques and methods well known in the art, and according to techniques and methods described in the references cited in this specification, e.g., as described in Sambrook et al molecular Cloning: A Laboratory Manual (3 rd ed., cold Spring Harbor Laboratory Press, cold Spring Harbor, n.y. (2001)). All references cited herein, including patents, patent applications, articles, textbooks, and the like, and the references cited therein, are hereby incorporated by reference in their entirety.
Abbreviations used herein
In one aspect, the invention provides a method of predicting whether a subject, i.e., a HER2 positive T1N0 breast invasive ductal carcinoma patient, has a poor prognosis, comprising:
calculating or determining whether the determined age of the subject is greater than or equal to 40 years old or less,
determining a stage of breast cancer in the subject or receiving a stage of breast cancer in the subject, wherein the stage of breast cancer is T1a, T1b, T1c or T1mi,
measuring the ER/PR status of or receiving the ER/PR status of the breast cancer in the subject, wherein the ER/PR status is ER+PR-, R-PR-, ER-PR+ or ER+PR+,
-measuring the Ki-67 expression level of breast cancer in the subject or receiving whether the Ki-67 expression level of breast cancer in the subject is 30% or more or less, and
-comparing the information obtained by the above modules with the correspondence information shown in fig. 1 to obtain an age score, a stage score, an ER/PR status score and a Ki-67 expression score;
calculate total score = age score + stage score + ER/PR status score + Ki-67 expression score,
if the total score is less than the cutoff value, indicating that the subject has a poor prognosis of breast cancer, if the total score is greater than the cutoff value, the prognosis is good, wherein the cutoff value is 40.0-50.0 points, preferably 42.7 points.
In one embodiment, the method comprises:
(1) The age of the diagnosis is less than 40 years old, and the age score is 0.0 score; the age of the diagnosis is greater than or equal to 40 years, and the age score is 70.0-72.5, preferably 71.1; and/or
(2) The stage of breast cancer is T1c, and the score of the stage is 0.0; the breast cancer stage is T1a or T1b, and the stage score is 60.0-62.5, preferably 60.8; the stage of the breast cancer is T1mi, and the score of the stage is 75.0-77.5, preferably 76.1; and/or
(3) ER/PR status scores were as follows:
ER+PR-:0.0 min
ER-PR-:32.5 to 35.0 minutes, preferably 33.1 minutes
ER-PR+:57.5 to 60.0 minutes, preferably 58.6 minutes
Er+pr+:90.0 to 92.5 minutes, preferably 91.0 minutes
And/or
(4) The Ki-67 expression level is 30% or more, and the Ki-67 expression score is 0.0 score; ki-67 expression levels of less than 30% gave Ki-67 expression scores of 37.5-40.0 points, preferably 37.8 points.
In one embodiment, the invention provides a method of predicting whether a HER2 positive T1N0 breast cancer in a subject is a poor prognosis breast cancer comprising:
calculating or obtaining a definitive age of the subject,
determining or obtaining a stage of breast cancer in the subject,
measuring or obtaining the ER/PR status of breast cancer in said subject,
-measuring or obtaining the level of Ki-67 expression of breast cancer in said subject, and
-assigning a respective score according to the information obtained by the above modules, wherein:
■ The age of the diagnosis is less than 40 years old, and the age score is 0.0 score; if the age is 40 years or more, giving an age score of 71.1 points;
■ The stage of breast cancer is T1c, and the score of the stage is 0.0; if the stage is T1a or T1b, the stage score is 60.8; if the stage is T1mi, the stage score is 76.1;
■ ER/PR status assignment scores were as follows:
● ER+PR-:0.0 min
● ER-PR-:33.1 minutes
● ER-PR+:58.6 minutes
● Er+pr+:91.0 min
■ If the Ki-67 expression level is greater than or equal to 30%, the Ki-67 expression score is given as 0.0 score, and if the Ki-67 expression level is less than 30%, the Ki-67 expression score is given as 37.8 score;
calculating a total score = age score + staging score + ER/PR status score + Ki-67 expression score, if the total score is less than a cutoff value, indicating that the subject's breast cancer prognosis is poor, if the total score is greater than the cutoff value, the prognosis is good, wherein the cutoff value is 40.0-50.0 points,
preferably 42.7 minutes.
In one embodiment, the stage of breast cancer and or ER/PR status and or Ki-67 expression level are determined by measuring a biological sample of breast cancer from a subject.
In one aspect, the invention provides an apparatus for predicting whether a subject, i.e., a HER2 positive T1N0 breast invasive ductal carcinoma patient, has a poor prognosis, comprising:
a module for calculating or receiving whether the determined age of the subject is greater than or equal to 40 years old or less,
a module for determining a stage of breast cancer in the subject or receiving a stage of breast cancer in the subject, wherein the stage of breast cancer is T1c, T1a, T1b or T1mi,
A module for measuring the ER/PR status of or receiving the ER/PR status of breast cancer in said subject, wherein ER/PR status is ER+PR-, R-PR-, ER-PR+ or ER+PR+,
-a module for measuring the expression level of Ki-67 of breast cancer in said subject or for receiving whether the expression level of Ki-67 of breast cancer in said subject is 30% or more, and
-comparing the information obtained by the above modules with the correspondence information shown in fig. 1, obtaining an age score, a stage score, an ER/PR status score and a Ki-67 expression score, preferably the apparatus comprises a module for storing or obtaining the correspondence information shown in fig. 1;
a module for calculating a total score = age score + staging score + ER/PR status score + Ki-67 expression score,
a module for displaying a total score of said subject and/or indicating a prognosis prediction of breast cancer, if the total score is less than a cut-off value, indicating that the prognosis of said subject is poor, if the total score is greater than a cut-off value, the prognosis is good, wherein the cut-off value is 40.0-50.0 points, preferably 42.7 points,
-optionally comprising, if the subject's prognosis is poor, suggesting administration of adjuvant chemotherapy and/or adjuvant-targeted therapeutic modules to the subject.
In one embodiment, the invention provides an apparatus for predicting whether a subject, i.e., a HER2 positive T1N0 breast invasive ductal carcinoma patient, has a poor prognosis comprising:
a module for calculating or receiving a definite age of the subject,
a module for determining or receiving a stage of breast cancer in said subject,
a module for measuring or receiving the ER/PR status of breast cancer in said subject,
-a module for measuring or receiving the expression level of Ki-67 of breast cancer in said subject, and
-assigning a respective score according to the information obtained by the above modules, wherein:
■ The age of the diagnosis is less than 40 years old, and the age score is 0.0 score; if it is 40 years or more, an age score of 70.0-72.5 points, preferably 71.1 points is given;
■ The stage of breast cancer is T1c, and the score of the stage is 0; if the stage is T1a or T1b, a stage score of 60.0 to 62.5, preferably 60.8 is assigned; if the stage is T1mi, a stage score of 75.0-77.5, preferably 76.1 is assigned;
■ ER/PR status assignment scores were as follows:
● ER+PR-:0.0 min
● ER-PR-:32.5 to 35.0 minutes, preferably 33.1 minutes
● ER-PR+:57.5 to 60.0 minutes, preferably 58.6 minutes
● Er+pr+:90.0 to 92.5 minutes, preferably 91.0 minutes
■ Ki-67 expression levels, if 30% or more, give a Ki-67 expression score of 0.0 points, if less than 30% give a Ki-67 expression score of 37.5-40.0 points, preferably 37.8 points;
Calculating a total score = age score + period score + ER/PR status score + Ki-67 expression score, if the total score is less than a cut-off value, indicating that the subject has a poor prognosis, if the total score is greater than a cut-off value, the prognosis is good, wherein the cut-off value is 40.0-50.0 points, preferably 42.7 points,
-optionally comprising a module recommending that the subject receive adjuvant targeted therapy and/or receive a more therapeutic chemotherapeutic regimen if the subject has a poor prognosis.
In one embodiment, the stage of breast cancer and or ER/PR status and or Ki-67 expression level are determined by measuring a biological sample of breast cancer from a subject.
As used herein, the term "T1N0" refers to a stage of T1N0 according to the united states cancer joint committee for breast cancer (AJCC) 8 th edition of stage criteria.
As used herein, HER2 positive is defined as Immunohistochemical (IHC) staining of post-operative pathology to 3+ or immunofluorescent in situ hybridization (FISH) of post-operative pathology to amplification (Wolff AC et al Recommendations for human epidermal growth factor receptor 2 testing in breast cancer:American Society of Clinical Oncology/Collegeof American Pathologists clinical practice guideline update. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2013; 31:3997-4013).
The term "HER2" refers to human EGFR-2 (Human Epidermal Growth Factor Receptor 2,GenBank Accession Number NP 004439) encoding product ERBB2 (GenBank Accession Number NM 004448.4, etc.). HER2 is a transmembrane protamine of 185kD, abbreviated as p185, consisting of 1255 amino acids, belonging to the tyrosine kinase domain at positions 720-987. HER2 protein is a transmembrane protein with tyrosine protein kinase activity, belonging to one of the EGFR family members. The protein consists of three parts, namely an extracellular ligand binding region, a single-chain transmembrane region and an intracellular protein tyrosine kinase region, no known ligand exists, and HER2 protein plays a corresponding physiological role mainly through the formation of homo-or hetero-dimers with family members including EGFR (HERl/erbB 1), HER3/erbB3 and HER4/erbB4, the conformation changes after dimerization, the intracellular tyrosine kinase activity is activated, and then the downstream pathway is activated. The HER2 protein mediated signal transduction pathway mainly comprises a Ras/Raf/Mitogen Activated Protein Kinase (MAPK) pathway, a phosphatidylinositol 3-hydroxy kinase (PI 3K)/Akt pathway, a signal transduction and transcription activation (STAT) pathway, a PLC pathway and the like.
In one embodiment, the HER2 positive T1N0 breast invasive ductal carcinoma patient is a patient diagnosed with invasive breast cancer and undergoing radical breast cancer surgery. The post-operative pathology of breast cancer in these patients showed: histological types are invasive ductal carcinoma, pathologically staged as T1N0, immunohistochemistry and/or immunofluorescence in situ hybridization showed HER2 positivity. It should be noted that the patient referred to is free of patients who received neoadjuvant therapy (e.g., neoadjuvant chemotherapy, neoadjuvant radiotherapy, neoadjuvant targeted therapy, and neoadjuvant endocrine therapy) prior to radical surgery.
In this context, poor prognosis means that the subject's 5-year IDFS survival rate or 6.5-year IDFS survival rate is less than 95% or less, while good prognosis means that the subject's 5-year IDFS survival rate or 6.5-year IDFS survival rate is greater than 95% or more. In one embodiment of the present invention, with 95% of 5-year IDFS survival as the prognostic threshold, poor prognosis means that the 5-year IDFS survival is less than 95% and good prognosis means that the 5-year IDFS survival is greater than 95%. In a preferred embodiment, good prognosis means that the subject has a 5 year IDFS survival or a 6.5 year IDFS survival of greater than 99%.
According to the correspondence information shown in fig. 1, the 5-year IDFS survival rate of 95% corresponds to a total score of between 40.0 and 50.0 minutes, more precisely about 42.7 minutes. Herein, a score of between 40.0 and 50.0 points, preferably 42.7 points, may be selected as a cut-off value for judging that the 5-year IDFS survival is lower or higher than 95%, and when the total score is lower than the cut-off value, the 5-year IDFS survival is considered to be lower than 95%, and when the total score is higher than the cut-off value, the 5-year IDFS survival is considered to be higher than 95%.
According to the correspondence information shown in fig. 1, the 6.5 year IDFS survival rate of 95% corresponds to a total score of between 60.0 and 65.0 minutes, more precisely about 62.1 minutes. Thus, a score between 60.0 and 65.0 points, preferably 62.1 points, may be selected as a cutoff for determining that 6.5 year IDFS survival is less than or greater than 95%, with 6.5 year IDFS survival being considered to be less than 95% when the total score is less than the cutoff and 6.5 year IDFS survival being considered to be greater than 95% when the total score is greater than the cutoff. In one embodiment of the present invention, with 95% 6.5 year IDFS survival as the prognostic threshold, poor prognosis means that 6.5 year IDFS survival is less than 95% and good prognosis means that 6.5 year IDFS survival is greater than 95%.
According to the correspondence information shown in fig. 1, the 5-year IDFS survival rate of 99% corresponds to a total score of about 160.0 (more precisely about 160.8), while the 6.5-year IDFS survival rate of 99% corresponds to a score of 180.0-185.0, more precisely about 180.3. Thus, in one embodiment, a total score below the cutoff 160.0 (more precisely 160.8) is considered a 5 year IDFS survival of less than 99%, while a total score above the cutoff 160.0 (more precisely 160.8) is considered a 5 year IDFS survival of greater than 99%, or a total score below the cutoff (180.0-185.0 minutes, more precisely 180.3) is considered a 6.5 year IDFS survival of less than 99%, and a total score above the cutoff (180.0-185.0 minutes, more precisely 180.3) is considered a 6.5 year IDFS survival of greater than 99%.
As used herein, the term "definitive age" refers to the age of a subject at the time of radical surgery for breast cancer.
Herein, calculating or receiving the diagnostic age of the subject may be accomplished by any method known in the art, such as calculating based on the subject's birthday and the surgical time the subject has received or directly obtaining the subject's filled diagnostic age.
Herein, the information of the subject's breast cancer stage may be obtained from a pathology detection report of the subject. Alternatively, the breast cancer stage of the subject may be determined using any method known in the art, such as pathological examination of the patient's post-operative tissue, measuring the maximum diameter of invasive breast cancer lesions and counting the number of lymph node metastases.
As used herein, the term "breast cancer stage" refers to a subject having a T1N0 breast cancer that is classified as stage standard according to united states joint committee for cancer (AJCC) 8 th Edition (American College of Surgeons2017, m.b. amin et al (eds.), AJCC Cancer Staging Mannul, weight Edition, DOI 10.1007/978-3-319-40618-3_48) as stage T1a, T1b, T1c, or T1 mi.
As used herein, the terms "T1a", "T1b", "T1c" and "T1mi" refer to a patient's post-operative pathological specimens showing invasive breast cancer with a maximum diameter of greater than 0.1cm and less than or equal to 0.5cm, greater than 0.5cm and less than or equal to 1.0cm, greater than 1.0cm and less than or equal to 2.0cm and less than or equal to 0.1cm, respectively (united states joint committee for cancer (AJCC) 8 th edition).
As used herein, the term "ER" refers to the human estrogen receptor, the predominant type of which, erα (GenBank: AAA 52399.1), is located in the nucleus and when estradiol binds to its ligand binding region, it causes conformational changes in the ER, thereby recruiting co-regulatory proteins to regulate gene transcription and promote tumor cell growth, proliferation and survival.
As used herein, the term "PR" refers to the human progestin receptor (GenBank: AAA 60081.1), which belongs to the steroid receptor superfamily that regulates cellular function upon binding of progestin.
As used herein, "ER+" or "PR+" refers to a ratio of cells having ER or PR expression to total tumor cells of greater than or equal to 1% and less than 1% is "ER-" or "PR-" in a breast cancer tissue, such as a biological sample of breast cancer. ( "American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cance", JOURNAL OF CLINICAL ONCOLOGY, volume 28 No.16, p2784-2795, june 1 2010; instructions for the immunohistochemical detection of breast cancer estrogen and progestin receptors, pages 237-239, volume 44, 4, month, 2015, J.P. of Chinese pathology " )
As used herein, the term "Ki-67" is a nuclear antigen associated with cell proliferation encoded by the MKI67 gene, which has two isoforms: isoform 1 (NCBI Reference Sequence: NP-002408.3) and isoform 2 (NCBI Reference Sequence: NP-001139438.1), whose functions are closely related to mitosis, are indispensable in cell proliferation.
As used herein, the term "Ki-67 expression level" refers to the ratio of the Ki-67 protein-staining positive cells to the total tumor cells in breast cancer tissue ("China anticancer Association's diagnostic guidelines and Specification for breast cancer (2021 edition)", "J.China cancer, volume 31, 10, pages 954-1040;" China clinical society for tumor (CSCO) diagnostic guidelines 2021, ministry of health, 2021.3, ISBN 978-7-117-31386-5;); "Personalizing the treatment of women with early breast cancer: highlightsof the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013", annals of Oncology 24:2206-2223,2013, doi:10.1093/annonc/mdt 303). For example, a Ki-67 expression level of 30% or greater means that the proportion of cells positive for Ki-67 protein staining in breast cancer tissue, such as a biological sample of breast cancer, is 30% or greater based on the total tumor cell count.
Herein, ER/PR status and Ki-67 expression levels in a biological sample of breast cancer can be determined by immunohistochemical methods, or from post-operative pathology reports from the subject.
In one embodiment, ER/PR status and/or Ki-67 expression levels in a biological sample of breast cancer can be detected using specific antibodies.
As used herein, the terms "antibody", "antigen binding fragment" or "immunogenic portion" are intended to have meanings commonly known to those skilled in the art. See Fundamental Immunology, ch.7 (Paul, W., ed., 2 nd edition, raven Press,. Y. (1989), which is incorporated herein by reference in its entirety, specific antibodies to HER2 protein, ER protein, PR protein and Ki-67 protein may be obtained by those skilled in the art.
In one embodiment, immunohistochemical (IHC) staining is used to assess expression of ER, PR, HER2 and Ki-67.
In one embodiment, ER+ or PR+ refers to a IHC staining ratio of ∈1% or more for ER or PR in a breast cancer, e.g., breast cancer biological sample, while "ER-" or "PR-" refers to an IHC staining ratio of <1% for ER or PR in a breast cancer tissue, e.g., breast cancer biological sample. The ratio is the ratio of the number of positively stained cells to the total tumor cells.
In one embodiment, a Ki-67 expression level of 30% or greater refers to a ratio of the number of IHC-stained cells of Ki-67 to the total tumor cells of greater than or equal to 30% in a breast cancer tissue, such as a biological sample of breast cancer.
As used herein, "subject" and "patient" are used interchangeably to refer to a human subject suffering from breast HER2 positive T1N0 invasive ductal carcinoma. In one embodiment, the subject is a subject who has undergone a breast cancer procedure, such as a radical breast cancer procedure.
As used herein, the "breast cancer biological sample" is any biological sample of breast cancer from a test subject, particularly a tumor tissue sample comprising a nucleic acid or polypeptide. The sample used for detection in the method of the invention should generally be collected in a clinically acceptable manner, e.g. in a manner that protects cells, nucleic acids or proteins. The sample may also be pretreated to increase accessibility of the target molecules, such as by lysis (mechanical, chemical, enzymatic, etc.), purification, centrifugation, separation, etc. The sample may also be labeled to facilitate detection of the presence of the target molecule (fluorescent, radioactive, luminescent, chemical, enzymatic labels, etc.). It is also contemplated that the subject's tissues and/or cells have been taken from the subject and, for example, have been placed on a microscope slide, and that the claimed methods are performed on the slide.
In one embodiment, the breast cancer biological sample is a breast cancer tissue sample, such as a breast cancer tissue slice.
In a preferred embodiment, the determination of whether the subject has a stage of breast cancer, ER/PR status and Ki-67 expression level of 30% or more is based on a post-operative pathological report from the subject.
Comparing the information such as the diagnosis age, breast cancer stage, ER/PR state and Ki-67 expression level with the corresponding relation information shown in the figure 1, and obtaining the score according to the corresponding relation information shown in the figure 1. The correspondence information shown in fig. 1 may be transformed into various suitable types such as extracted as tables, graphs, numerical ranges, etc. for comparison and obtaining corresponding scores according to any manner known to those skilled in the art.
Fig. 1 shows the scores corresponding to the parameters in the prognosis model according to the invention, wherein the values of the points of the vertical projection of the marked parameter points on the "score" line are used as the corresponding scores. The score line has a minimum of 2.5 minutes as the partition interval, and thus, in one embodiment, the score of a parameter may be any value within the interval range of the point of which the perpendicular projection falls. Preferably, the value corresponding to the proxel may be further determined precisely (within a range of errors that can be reasonably determined by one skilled in the art) to determine the score.
For example, if the projection point of the parameter point with the age equal to or greater than 40 years old on the score line is located in the range of 70.0-72.5, the age score with the age equal to or greater than 40 years old may be any value between 70.0 and 72.5. The more accurate projection point of the parameter point of the diagnosis age of 40 years or more on the score line is about 71.1, so in the preferred embodiment, the diagnosis age of 40 years or more is 71.1.
In one embodiment, the subject has an age score of 0.0 score when the subject is diagnosed with an age of less than 40 years old, and an age score of 70.0-72.5 score, more precisely 71.1 score when the subject is greater than or equal to 40 years old, according to fig. 1.
In one embodiment, for a T1a or T1b split, 60.0 to 62.5 minutes, more precisely 60.8 minutes; for the T1mi period, it is 75.0-77.5 minutes, more precisely 76.1 minutes.
In one embodiment, for ER-PR-, 32.5 to 35.0 minutes, more precisely 33.1 minutes; for ER-PR+, 57.5-60.0 minutes, more precisely 58.6 minutes; for ER+PR+, it is 90.0 to 92.5 minutes, more precisely 91.0 minutes.
In one embodiment, the Ki-67 expression level is less than 30%, 37.5 to 40.0 minutes, more precisely 37.8 minutes.
In a preferred embodiment, the apparatus includes a module for storing or retrieving correspondence information as shown in fig. 1. The module may store correspondence information such as states of respective parameters and respective scores shown in fig. 1, so that scores are respectively assigned according to the obtained definite ages of 40 years or less, breast cancer stages of T1c, T1a, T1b or T1mi, ER/PR states of er+pr-, R-PR-, ER-pr+ or er+pr+ and Ki-67 expression levels of 30% or more. Alternatively, the device may obtain such information from other sources, such as a remote server, complete the comparison and obtain a score accordingly.
In one embodiment, the adjuvant targeted therapy refers to the use of specific anti-HER 2 mab trastuzumab.
In one embodiment, the chemotherapy is a chemotherapy regimen with an anthracycline or a chemotherapy regimen with a non-anthracycline.
In one embodiment, the apparatus may be used to provide patient or related personal cues by interfacing with a digital processing device (e.g., a personal data assistant or smart phone, a notebook computer, a desktop computer, a tablet computer or device, a remote web server, etc.).
As used herein, a module that displays the measurement results may inform the subject or related medical personnel of the measurement results (e.g., greater or less than, or a specific value, etc.) in any suitable manner (e.g., alert tones, digital signals, networking messages, etc.), including, for example, a display screen, etc.
The apparatus may be interconnected with other systems including, but not limited to, smartphones, tablets, notebooks, and combinations of computing devices and cloud computing resources.
In one embodiment, the breast cancer biological sample is a breast cancer tissue sample, such as a breast cancer tissue slice.
In one aspect, the invention provides a method of treating a HER2 positive T1N0 breast invasive ductal carcinoma subject comprising performing a method of predicting whether a subject, i.e., a HER2 positive T1N0 breast invasive ductal carcinoma patient, is not prognosis-good according to the invention, and if the subject is not prognosis-good, recommending the subject to receive adjuvant targeted therapy and/or to receive a more therapeutic chemotherapy regimen.
In one embodiment, the adjuvant targeted therapy refers to the use of specific anti-HER 2 mab trastuzumab.
In one embodiment, the chemotherapy is a chemotherapy regimen with an anthracycline or a chemotherapy regimen with a non-anthracycline.
In one aspect, the invention provides an apparatus comprising a digital processor configured to perform the method of predicting whether a subject, i.e., a HER2 positive T1N0 breast invasive ductal carcinoma patient, is prognosis poor and/or the method of treating a HER2 positive T1N0 breast invasive ductal carcinoma subject of the invention.
In one aspect, the invention provides a non-transitory storage medium storing instructions executable by a digital processing device to perform a method of predicting whether a subject, i.e., a HER2 positive T1N0 breast invasive ductal carcinoma patient, is prognosis poor and/or a method of treating a HER2 positive T1N0 breast invasive ductal carcinoma subject as described herein.
In one aspect, the present invention provides a computer program comprising program code means for causing a digital processing device to carry out the method of predicting whether a subject, i.e. a HER2 positive T1N0 breast invasive ductal carcinoma patient, is not prognosis good and/or the method of treating a HER2 positive T1N0 breast invasive ductal carcinoma subject according to the present invention, when the digital processing device runs the computer program.
In one embodiment, the non-transitory storage medium stores instructions executable by a digital processing device to perform a method as described herein. The non-transitory storage medium may be a computer-readable storage medium such as a hard disk drive or other magnetic storage medium, an optical disk or other optical storage medium, random Access Memory (RAM), read-only memory (ROM), flash memory, or other electronic storage medium, a network server, etc. The digital processing device may be a handheld device (e.g., a personal data assistant or a smart phone), a notebook computer, a desktop computer, a tablet computer or device, a remote web server, or the like.
In one embodiment, the computer program comprises program code means for causing a digital processing apparatus to perform the method as described herein when the computer program is run on the digital processing apparatus. The digital processing device may be a handheld device (e.g., a personal data assistant or a smart phone), a notebook computer, a desktop computer, a tablet computer or device, a remote web server, or the like.
Embodiments of the apparatus and methods described herein may be implemented in a variety of systems including, but not limited to, smartphones, tablets, notebooks, and combinations of computing devices and cloud computing resources. For example, some operations may occur in one device, while other operations may occur at a remote location, such as one or more remote servers. For example, the collection of data may be performed at a smartphone, and the data analysis may be performed at a server or cloud computing resource. Any single computing device or combination of computing devices may perform the methods.
As used herein, "optionally present" or "optionally" means that the subsequently described event or circumstance occurs or does not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
Examples
The invention is further illustrated by the following examples, but any examples or combinations thereof should not be construed as limiting the scope or embodiments of the invention.
Example 1:
this retrospective study was conducted in tumor hospitals at the national academy of medical science. The study included consecutive breast cancer patients who were pathologically confirmed to be HER2 positive invasive ductal carcinoma at the national academy of medical science oncology hospital from month 4 2010 to month 4 2017. Other inclusion criteria were: breast cancer radical surgery has been performed and the pathology demonstrated a stage of T1N0 according to united states joint committee for cancer (AJCC) version 8. The exclusion criteria included: distant metastasis is found at diagnosis or within 1 month of radical surgery treatment; any neoadjuvant therapy (including systemic treatment or radiotherapy in internal medicine); in addition to papillary thyroid carcinoma, breast cancer was diagnosed with other malignant tumors than breast cancer from 5 years before to half a year after radical surgery (Mazzaferri EL, jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 1994; 97:418-28); the visit was lost after the operation.
Data collection and outcome index
Researchers retrieve and acquire data from hospital information systems. Information on tumor size, lymph node status, vascular tumor plug (LVI), histological type, histological grade, and expression of Estrogen Receptor (ER), progestin Receptor (PR), HER2 and Ki-67 was extracted from the pathology report. According to post-operative pathology reports, all patients were re-staged according to the AJCC staging standard version 8. Researchers also collect data in the medical record system such as age, menstrual status, radical surgery time, surgical mode, adjuvant therapy, recurrence status, and review information at the time of patient diagnosis. In addition, researchers follow-up with patients admitted to the group by telephone or text messages.
According to the second edition of international consensus for young female Breast cancer, researchers defined patients aged 40 or less as young Breast cancer patients (Paluch-Shimon S et al, ESO-ESMO 3rd international consensus guidelines for Breast cancer in young women (BCY 3). Breast (Edinburgh, scotland) 2017; 35:203-17). Tumor size is defined as the largest diameter of the tumor-infiltrating portion. Immunohistochemical (IHC) staining was used to evaluate the expression of ER, PR, HER and Ki-67. ER and PR were defined as positive at > 1%. HER2 positivity is defined as IHC3+ or immunofluorescence in situ hybridization (FISH) as amplification (Wolff AC et al Recommendations for human epidermal growth factor receptor 2 testing in breast cancer:American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2013; 31:3997-4013). Ki-67 staining was defined as high expression > 30% and < 30% as low expression (Nielsen TO et al, assembly of Ki67 in Breast Cancer: updated Recommendations From the International Ki67 in Breast Cancer Working group. Journal of the National Cancer Institute 2021;113: 808-19).
The main study outcome of the study was IDFS. Other research outcomes include: remote disease free survival (DDFS), relapse Free Survival (RFS), remote relapse free survival (DRFS), and total survival (OS). Event definition at the end of the study is referred to efficacy endpoint criteria Version 2.0 (Tolaney SM et al Updated Standardized Definitions for Efficacy End Points (STEEP) in Adjuvant Breast Cancer Clinical Trials: STEEP Version 2.0. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2021; 39:2720-31). All study outcomes were defined as the time from radical surgical excision to the time of event occurrence. The non-occurrence of a relevant event for the last follow-up is defined as a deletion.
Statistical analysis
First, the investigator described baseline characteristics of the incorporated HER2 positive T1N0 breast cancer patients. Researchers performed multi-factor analysis using a Cox risk regression model for different endpoint metrics and calculated the risk ratio (HR) and 95% Confidence Interval (CI) for each factor. Inclusion factors include: age, type of surgery (breast-conserving or total mastectomy), histological grading, T-staging, LVI, ER/PR status, ki-67, whether to receive adjuvant chemotherapy and whether to receive adjuvant trastuzumab. Based on the Cox analysis above, researchers selected factors with P values less than 0.1 as prognostic-related factors for T1N0 breast invasive ductal carcinoma. And then, the researchers select a group without the loss of the data of the prognosis related factors from all groups which are included in the prognosis analysis, and according to the data of the group, a multi-factor risk prediction model about IDFS is established and displayed by using a nomogram.
All statistical analyses used R software, version 4.1.0. The P values are both double-sided values. P <0.05 is considered statistically significant. Survival analysis and Cox analysis used the "survivinal" package (Therneau. A Package for Survival Analysis in R, 2021), and alignment was drawn using the "rms" package (Frank E Harrell Jr (2021): rms: regression Modeling structures.R package version 6.2-0. Https:// CRAN.R-project.org/package = rms).
Results
Baseline characteristics of population as a whole
The study included 692 HER2 positive T1N0 invasive breast cancer patients in total. Baseline clinical pathology features are shown in table 1. 616 patients were diagnosed with an age above 40 years. There were 239 patients with primary tumor histologically graded 3, 435 patients with tumor graded T1c, 338 patients with ER+PR+, 448 patients with Ki-67.gtoreq.30% and 61 patients with LVI. Note that LVI information was missing in 356 patients, since LVI was not routinely recorded in pathology reports early in 2010.
Prognosis factor analysis
For IDFS, median follow-up was 78.0 months. Median follow-up for DDFS, RFS, DRFS was 78.0 months. For OS, median follow-up time was 77.8 months. The IDFS rate was 89.6% for 6.5 years (95 ci 87.2-92.0%), and 96% for 6.5 years of OS (95 ci 95.5-98.4%). There are a total of 72 IDFS events and 23 OS events occurring. The IDFS event composition categories are as follows: ipsilateral breast recurrence or local recurrence (23/72), distant metastasis (29/72), secondary non-breast primary carcinoma (11/72), contralateral invasive breast carcinoma (4/72), breast carcinoma, death from non-breast carcinoma or death from unknown cause (5/72). A total of 23 patients had a death event, 13 patients died from breast cancer. Table 3 summarizes the detailed constitution of the different survival outcomes.
Cox multifactor regression showed that age 40 years (hr=2.62, 95% ci 1.39-4.92, p=0.003) for IDFS, tumor stage T1c (hr=2.35, 95% ci 1.17-4.73, p=0.017) was an independent protective factor for patient prognosis. Meanwhile, er+pr+ (hr=0.44, 95% ci 0.26-0.77, p=0.004) and trastuzumab adjunctive (hr=0.21, 95% ci 0.12-0.35, p < 0.001) are independent protective factors for patient prognosis. For OS, high Ki-67 expression (hr=6.88, 95% ci 1.55-30.62 p=0.011) is an independent risk factor for poor prognosis, while adjuvant application of trastuzumab (hr=0.21, 95% ci 0.08-0.56, P < 0.001) is an independent protective factor for patient prognosis. The multi-factor analysis results of IDFS and other study outcomes are shown in table 2. In general, patients with age less than or equal to 40 years old (for IDFS and RFS), T1c (for IDFS, DDFS, RFS and DRFS), high Ki-67 expression (for RFS, DRFS and OS) had a poor prognosis; whereas patients with er+pr+ have a better prognosis (for IDFS, DDFS, RFS, DRFS). Adjuvant trastuzumab therapy is an independent protective factor for patients for all endpoint events. Based on Cox multifactorial analysis of the clinical pathology, researchers established a prognostic risk model for IDFS for HER2 positive T1N0 invasive ductal carcinoma patients and were demonstrated by nomograms (fig. 1).
TABLE 1 characteristic baseline tables incorporated into patients in prognostic assays
a IDC: invasive ductal carcinoma; b LVI, vascular tumor plug; c ER: an estrogen receptor; d PR: progestogen receptor
TABLE 3 initial event number, median follow-up and event-free survival for different study outcomes
a IDFS: no infiltration exists; b DDFS: distant disease-free survival; c RFS: the survival without recurrence; d DRFS: distant survival without recurrence; e OS: total survival; f IBTR: invasive ipsilateral breast tumor; g CI: confidence interval.
Claims (10)
1. An apparatus for predicting whether a subject, HER2 positive T1N0 breast invasive ductal carcinoma patient, has a poor prognosis comprising:
a module for calculating or determining whether the determined age of the subject is greater than or equal to 40 years old or less,
a module for determining a stage of breast cancer in the subject or receiving a stage of breast cancer in the subject, wherein the stage of breast cancer is T1a, T1b, T1c or T1mi,
a module for measuring the ER/PR status of or receiving the ER/PR status of breast cancer in said subject, wherein ER/PR status is ER+PR-, ER-PR-, ER-PR+ or ER+PR+,
-a module for measuring the expression level of Ki-67 of breast cancer in said subject or for receiving whether the expression level of Ki-67 of breast cancer in said subject is 30% or more, and
-means for obtaining an age score, a stage score, an ER/PR status score and a Ki-67 expression score from the above obtained information in comparison with the correspondence information shown in fig. 1, preferably the apparatus comprises means for storing or enabling to obtain the correspondence information shown in fig. 1;
a module for calculating a total score = age score + staging score + ER/PR status score + Ki-67 expression score,
a module for displaying the total score of the subject and/or indicating a prognosis prediction result, if the total score is less than a cut-off value, indicating that the subject is not prognosis good, if the total score is greater than a cut-off value, wherein the cut-off value is 40.0-50.0 points, preferably 42.7 points,
optionally comprising a module that prompts a recommendation to the subject to receive adjuvant targeted therapy and/or to receive a more therapeutic chemotherapeutic regimen if the subject has a poor prognosis.
2. The apparatus of claim 1, wherein:
(1) Age less than 40 years old, age score 0.0 score; age equal to or greater than 40 years old, and age score of 70.0-72.5 score, preferably 71.1 score; and/or
(2) The stage of breast cancer is T1c, and the score of the stage is 0.0; the breast cancer stage is T1a or T1b, and the stage score is 60.0-62.5, preferably 60.8; the stage of the breast cancer is T1mi, and the score of the stage is 75.0-77.5, preferably 76.1; and/or
(3) ER/PR status scores were as follows:
ER+PR-:0.0 min
ER-PR-:32.5 to 35.0 minutes, preferably 33.1 minutes
ER-PR+:57.5 to 60.0 minutes, preferably 58.6 minutes
Er+pr+:90.0 to 92.5 minutes, preferably 91.0 minutes
And/or
(4) The Ki-67 expression level is 30% or more, and the Ki-67 expression score is 0.0 score; ki-67 expression levels of less than 30% gave Ki-67 expression scores of 37.5-40.0 points, preferably 37.8 points.
3. The device of claim 1 or 2, wherein the staging and/or measuring ER/PR status and/or Ki-67 expression level is determined by measuring a biological sample of breast cancer, such as a tissue sample of breast cancer, in particular a tissue section of breast cancer.
4. The device of any one of claims 1-3, wherein the adjuvant targeted therapy is administration of trastuzumab and the adjuvant chemotherapy is administration of an anthracycline and/or non-anthracycline anti-tumor chemotherapeutic.
5. An apparatus comprising a digital processor configured to perform a method comprising:
calculating or determining whether the determined age of the subject is greater than or equal to 40 years old or less,
determining a stage of breast cancer in the subject or receiving a stage of breast cancer in the subject, wherein the stage of breast cancer is T1a, T1b, T1c or T1mi,
Measuring the ER/PR status of or receiving the ER/PR status of the breast cancer in the subject, wherein the ER/PR status is ER+PR-, ER-PR-, ER-PR+ or ER+PR+,
-measuring the Ki-67 expression level of breast cancer in the subject or receiving whether the Ki-67 expression level of breast cancer in the subject is 30% or more or less, and
-obtaining an age score, a stage score, an ER/PR status score and a Ki-67 expression score based on comparing the above obtained information with the correspondence information shown in fig. 1;
calculating a total score = age score + period score + ER/PR status score + Ki-67 expression score, if the total score is less than a cut-off value, suggesting that the subject is not prognosis good, if the total score is greater than a cut-off value, wherein the cut-off value is 40.0-50.0 score, preferably 42.7 score,
-optionally, if the subject's prognosis is poor, prompting recommendation of the subject to receive adjuvant targeted therapy and/or to receive a more therapeutic chemotherapeutic regimen.
6. A non-transitory storage medium storing instructions executable by a digital processing apparatus to perform the method defined in claim 5.
7. A computer program comprising program code means for causing a digital processing device to carry out the method as defined in claim 5 when said computer program is run by the digital processing device.
8. The apparatus of claim 5, the non-transitory storage medium of claim 6, or the computer program of claim 7, wherein:
(1) The age of the diagnosis is less than 40 years old, and the age score is 0.0 score; the age of the diagnosis is greater than or equal to 40 years, and the age score is 70.0-72.5, preferably 71.1; and/or
(2) The stage of breast cancer is T1c, and the score of the stage is 0.0; the breast cancer stage is T1a or T1b, and the stage score is 60.0-62.5, preferably 60.8; the stage of the breast cancer is T1mi, and the score of the stage is 75.0-77.5, preferably 76.1; and/or
(3) ER/PR status scores were as follows:
ER+PR-:0.0 min
ER-PR-:32.5 to 35.0 minutes, preferably 33.1 minutes
ER-PR+:57.5 to 60.0 minutes, preferably 58.6 minutes
Er+pr+:90.0 to 92.5 minutes, preferably 91.0 minutes
And/or
(4) The Ki-67 expression level is 30% or more, and the Ki-67 expression score is 0.0 score; ki-67 expression levels of less than 30% gave Ki-67 expression scores of 37.5-40.0 points, preferably 37.8 points.
9. The device of claim 5, the non-transitory storage medium of claim 6 or the computer program of claim 7, wherein the staging and/or measuring ER/PR status and/or Ki-67 expression level is determined by measuring a breast cancer biological sample, such as a breast cancer tissue sample, in particular a breast cancer tissue section.
10. The device of claim 5, the non-transitory storage medium of claim 6, or the computer program of claim 7, wherein the adjuvant therapy is administration of trastuzumab and/or the chemotherapy is administration of an anthracycline and/or non-anthracycline.
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