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EP-4740014-A1 - METHOD FOR THE DETECTION OF CANCER

EP4740014A1EP 4740014 A1EP4740014 A1EP 4740014A1EP-4740014-A1

Abstract

The invention relates to uses and methods of distinguishing benign from malignant nodules comprising measuring cell free nucleosomes or components thereof.

Inventors

  • MICALLEF, JACOB VINCENT
  • BYGOTT, Thomas
  • CHEN, JIN-SHING
  • TSAI, Tung-Ming
  • CHEN, PEI-HSING

Assignees

  • Belgian Volition SRL

Dates

Publication Date
20260513
Application Date
20240703

Claims (20)

  1. 1. Use of a cell free nucleosome as a biomarker in a body fluid sample, for determining that a nodule in a subject is benign.
  2. 2. Use of a cell free nucleosome as a biomarker in a body fluid sample, for distinguishing benign nodules from malignant nodules in a subject.
  3. 3. The use as defined in any preceding claim, wherein the nodule is a pulmonary nodule.
  4. 4. The use as defined in any preceding claim, wherein the nodule is an indeterminate nodule.
  5. 5. The use as defined in any preceding claim, wherein the nodule has a diameter of less than or equal to about 2cm or less than or equal to about 3 cm.
  6. 6. The use as defined in claim 5, wherein the pulmonary nodule has a diameter of about 0.8 cm or about 1 cm to about 2 cm or about 3 cm.
  7. 7. The use as defined in any preceding claim, wherein the nodule is a malignant lung cancer nodule.
  8. 8. The use as defined in any preceding claim, wherein the nodule is a malignant nodule selected from squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, pleomorphic carcinoma or small cell carcinoma.
  9. 9. The use as defined in either of claims 7 or 8, wherein the malignant nodule is or is part of a cancer which is solid, micropapillary, lepidic, acinar or papillary.
  10. 10. The use as defined in any preceding claim, wherein the nodule is pre-cancer, minimally invasive cancer, Stage I (including Stage IA1, Stage IA2, Stage IA3 or Stage IB), Stage II, Stage III or Stage IV cancer.
  11. 11. The use as defined in any preceding claim, wherein the determination or distinction is conducted in conjunction with an imaging technique.
  12. 12. The use as defined in claim 11 , wherein the imaging technique is a computed tomography (CT) scan, an X-ray or a positron emission tomography (PET) scan.
  13. 13. The use as defined in claim 12, wherein the CT scan is a low dose computed tomography (LDCT) scan.
  14. 14. The use as defined in any one of claims 11 to 13, wherein the use is subsequent to the subject undergoing an imaging technique.
  15. 15. The use as defined in any preceding claim, wherein the subject is a smoker, an exsmoker or a non-smoker.
  16. 16. The use as defined in any preceding claim, wherein the cell free nucleosome is a mononucleosome or oligonucleosome.
  17. 17. The use as defined in any preceding claim, wherein the biomarker is the presence or level of cell free nucleosomes and/or an epigenetic feature of a cell free nucleosome.
  18. 18. The use as defined in claim 17, wherein the epigenetic feature of the cell free nucleosome is a histone isoform, such as a histone isoform of a core nucleosome, in particular a histone H3 isoform.
  19. 19. The use as defined in claim 18, wherein the histone isoform is H3.1.
  20. 20. The use as defined in claim 17, wherein the epigenetic feature of the cell free nucleosome is a histone post translational modification (PTM), such as a histone PTM of a core nucleosome, in particular a histone H3 PTM.

Description

METHOD FOR THE DETECTION OF CANCER FIELD OF THE INVENTION The invention relates to a body fluid test for the detection of cancer, particularly but not exclusively lung cancer patents, using a biomarker. The invention finds particular use in distinguishing between benign and cancerous nodules found during imaging. BACKGROUND OF THE INVENTION Lung cancer is a significant worldwide public health issue. Lung cancer has the highest mortality rate in many advanced countries including in Taiwan, Europe and the USA. The WHO reported that in 2020 lung cancer was the second most common cancer worldwide with 2.21 million cases (in terms of new cases). Cancer mortality is reduced when cases are detected and treated early. However, the majority of lung cancer patients present with inoperable, advanced disease entailing a poor prognosis. Advances in surgical, radiotherapeutic and chemotherapeutic approaches have been made, but the long-term survival rate remains at a low level in part due to late diagnosis. To reduce the high mortality rate of lung cancer, many experts promote lung cancer screenings based on the results of several trials (e.g., NELSON trial and the US National Lung Screening Trial). Such screening programmes employ low-dose computed tomography (LDCT) to reduce the radiation administered to the person screened. However, despite its high sensitivity, the specificity of CT in lung cancer diagnosis is poor. Notably, it has been reported that 24% of the LDCT screening exams produced a positive result, which required follow-up, but 96% of these findings were false positives (i.e., negative for lung cancer). This often leads to harmful and/or costly unintended consequences, such as repeated follow-up scans and invasive biopsies) (Park et al. Cancer (2013) 119:1306013; Thalanayer et al. Ann Am Thorc Soc (2015) 12:1193-6], Asymptomatic solitary pulmonary nodules revealed incidentally through a scan that was carried out for other reasons have also become a serious medical problem given the relatively large number of false positives. Again the potentially unnecessary invasive diagnostics in the case of benign pulmonary nodules reduces quality of life and increases anxiety. Therefore, it is critical to improve the discrimination of benign from malignant screen-detected lung nodules. The present invention meets a key unmet clinical need for the management of pulmonary nodules using a non-invasive diagnostic test that discriminates between malignant and benign indeterminate pulmonary nodules in patients. The test will be helpful in making correct clinical decisions and reduce the risk of unnecessary interventions. The test of the present invention may result in lowering healthcare costs which may allow screening programmes to be implemented more widely. STATEMENTS OF THE INVENTION According to a first aspect of the invention, there is provided a use of a cell free nucleosome as a biomarker in a body fluid sample, for determining that a nodule in a subject is benign. According to a further aspect of the invention, there is provided a use of a cell free nucleosome as a biomarker in a body fluid sample, for distinguishing benign nodules from malignant nodules in a subject. According to a further aspect of the invention, there is provided a method for determining that a nodule in a subject is benign, which comprises the steps of: (i) contacting a body fluid sample obtained from the subject with a binding agent to detect or measure cell free nucleosomes; and (ii) using the level of cell free nucleosomes detected to determine the nodule is benign. According to a further aspect of the invention, there is provided a method of distinguishing benign from malignant nodules in a subject with indeterminate nodules, which comprises the steps of: (i) contacting a body fluid sample obtained from the subject with a binding agent to detect or measure cell free nucleosomes; and (ii) using the level of cell free nucleosomes detected to determine the nodule is benign. According to a further aspect of the invention, there is provided a method of determining the likelihood that a nodule in a subject is not malignant, comprising: (i) contacting a body fluid sample obtained from the subject with a binding agent to detect or measure cell free nucleosomes; and (ii) using the level of cell free nucleosomes detected to determine whether the nodule is not malignant. According to a further aspect of the invention, there is provided a method of determining the likelihood that a nodule in a subject is not malignant, comprising: (i) measuring the presence or levels of cell free nucleosomes present in a body fluid sample obtained from the subject; (ii) calculating a probability of cancer score based on the presence or levels of the cell free nucleosomes measured in step (a); and (iii) ruling out cancer for the subject if the score in step (b) is lower than a predetermined score. According to a further aspect of the invention, there is provided a m