Origins and future of KDOG

Breast cancer: second leading cause of death among women in the world

After cardiovascular diseases, cancers constitute the second cause of death among women in the world, hitting one in seven women globally and being responsible for 14% of death worldwide in 2012^¹. Breast cancer is the most common cause of cancer death among women (522 000 deaths in 2012) and the most frequently diagnosed cancer among women in 140 of 184 countries worldwide. It now represents one in four of all cancers in women. The number of women concerned by cancer could dramatically increase by 2030. In 2012, two reports from American Cancer Society and The Lancet warned of an explosion in cancer deaths among women, with a toll, mainly from breast cancer, of around 5.5 million a year by 2030 – roughly the population of Denmark. This would represent a near 60% increase in less than two decades (3.5 million).^²^-^³

Hundreds of thousands of lives could be saved from cancer (lung, cervical, colorectal and breast) by improving the fight against smoking, fostering better nutrition and vaccination, and above all developing treatment and early screening. ACS report highlights the main vulnerabilities within poorer countries where access to diagnosis and treatment concern a very small proportion of cancer cases. Massive investment in favor of education, healthcare and prevention are required to stem the spread of the disease. Women in these countries are increasingly exposed to known cancer risk factors “associated with rapid economic transition”, said Sally Cowal^⁴, “such as physical inactivity, unhealthy diet, obesity, and reproductive factors” including postponing motherhood. Control of specific modifiable breast cancer risk factors (diet, physical activity, alcohol intake) could therefore reduce the impact of breast cancer in the long term, but ‘early detection in order to improve breast cancer outcome and survival remains the cornerstone of breast cancer control’^⁵ according to the WHO.

“An urgent need in cancer control today is to develop effective and affordable approaches to the early detection, diagnosis, and treatment of breast cancer among women living in less developed countries” Dr Christopher Wild, Director of the IARC, says^⁶.

In France, breast cancer triggered approximately 12,000 deaths in 2015^⁷ and 54 000 new cases were diagnosed during the year. However, when it is detected early, breast cancer is associated with good survival rates: on average 9 in 10 breast cancers are cured if treated early enough. Still, among the most exposed population (50-74 years-old women), 50% of French women choose not to participate in organized breast cancer screening program which propose a free mammography exam^⁸ and one third of them is neither followed regularly by a gynecologist. Early screening and prevention are major axes of breast cancer’s mortality reduction.

Genesis of the project

Everything started with the idea of one woman. Isabelle Fromantin joined the Curie Institute in 1993 where she worked as a nurse in pediatrics and ENT surgery before participating in the creation of the first mobile unit of Palliative Care in a Center for the Fight against Cancer in 1997. She is now a researcher associated with the Nursing Sciences Research Chair of the University Paris 13, Vice-President of the French and Francophone Society of Wounds and Healing until 2017 and member of several Scientific Committees.

The hypothesis: Volatile Organic Compounds as biomarkers for breast cancer

In 2009 Isabelle Fromantin starts a thesis about wounds and lesions caused by breast cancer. She focused her research more specifically on odors associated with malignant wounds. Indeed the human body naturally produces organic chemicals called Volatile Organic Compounds (VOCs). Malignant wounds also emit VOCs. Dr Fromantin thus came to one particular question: would it be possible to establish a link between the presence of particular odors (VOCs) and the presence of cancer cells?

“Volatile organic compounds are biomarkers produced by cancer cells. When going deeper into the study, the idea of an olfactory detection of breast cancer quickly became a main axis of my research” Dr Fromantin explains. Other researches in the scientific literature support this hypothesis that VOCs form biomarkers of cancer.

Therefore, being able to identify this specific olfactory signature would constitute an effective way to detect the presence of cancer. Why not then taking advantage of this correlation to develop transcutaneous sensors for cancer screening? But how could we identify and recognize an odor that is completely undetectable by human nose?

To analyze the scent emitted by malignant wounds, Isabelle Fromantin used two methods: analytical chemistry and canine olfactory detection. After comparison, the dog’s sense of smell seemed more acute and efficient than chemistry. Consequently, what if a dog was specially trained for cancer detection and put at work to find out cancer VOCs?

A multidisciplinary team

The meeting with a dog expert in 2011 gave its first impulsion to the KDOG project. A multidisciplinary team quickly constituted itself within the Curie Institute together with French engineering school ESPCI Paris. In 2015 caregivers from the Curie Institute (pathologists, nurses, cancer surgeons, anesthetists), scientific researchers in biology and chemistry (from ESPCI and Chimie Paris Tech) and dog experts (veterinarians, ethologists and dog-handlers) gathered to elaborate the research and place the olfactory sensibility of dogs at the service of medical progress.

KDOG, a disruptive initiative

A solidary label

Trained dogs for cancer detection are not new. In the US and in the UK, Dr. Gianluigi Taverna and his project Medical Dog Detection^⁹ worked at developing an early, accurate, non-invasive way to test for prostate and other urological cancers. The difference with our research essentially relies in the use of human body fluids (urine) for the dogs to analyze and find cancer odors. On the other hand, KDOG hopes to develop its screening method around the compress and to ensure a complete transcutaneous detection.

The KDOG project aims at creating a scientific label after solid evaluations, from the clinical study to the complete modelization of the process. This program wishes to be reproducible and solidary, therefore we will encourage the opening of KDOG-labelled cancer screening laboratories in emerging countries or elsewhere – even though the access to the label will be scrupulously controlled by KDOG and the Curie Institute and its accreditation procedures.

The KDOG method will be an « open source » project in accordance with the non-profit nature of the project.

A citizen-centered approach

The great involvement of citizens and volunteers from the civil society contributed to the originality of KDOG. This innovative research was launched thanks to the incredible generosity of the general public. 80,000€ were collected in 2016 through crowdfunding which enabled us to acquire our two first dogs. We hugely thank everybody for that! KDOG wants to stay an open and civic project and will continue to finance partly the clinical study through appeal to donations.

The absence of technology

Our choice of privileging canine detection instead of heavy technology to innovate in cancer screening constitutes a real disruptive decision. This corresponds to the team’s desire and the health authorities and the populations’ preferences for an inexpensive, easily mobilizable and accessible new detection technique. The use of heavy and sophisticated technology encompasses a risk of inequity in access to health, because of the important cost of the machine, making it unaffordable for many countries.

An innovative scientific challenge

Dog training: in August 2016, the first phase of the project was launched thanks to the participation of 130 women who allowed the collection of ‘sane’ and ‘cancer’ samples under the form of compresses. The samples were then sent to the training dog center where Nykios and Thor were ready to analyze them.
The proof of concept: during six months (August 16’-February 17’) the two dogs were educated to cancer detection and tested afterwards. The results of the test were greatly encouraging: a 100% success rate. These results were published on February 21^st 2017 and presented to the French National Academy of Medicine, to prove the scientific reliability of KDOG. This phase allowed us to answer two main questions: ‘does cancer have an odor?’ and ‘can the VOCs pass through the skin?’
The clinical study: planned between 2018 and 2020, this study will include 1,000 voluntary women to confirm KDOG’s sensibility tests.

The study will be conducted in two steps: we will start with 135 persons from each group to confirm the process’ efficiency. If the success rate is inferior to 80%, the study will be stopped and the project aborted. This is our condition to guarantee efficiency.
If KDOG receives the adequate funds: the team will be reinforced, five to seven health centres will join us and be included in the study to recruit patients. Two new dogs of a different pedigree will also be enrolled in KDOG. A study led by ethologist researchers from the French university ENVA will help us to set selection criteria for dogs. We will then be able to choose them efficiently before starting the training process and hence optimize their performances.
The protocol will also be improved about the transport means and the compress’ quality (material, production, size…).

KDOG goals

KDOG seeks to achieve different objectives:

Elaborating a transcutaneous method of early screening of cancer is the priority. This method should be simple, reliable and noninvasive.
Extending the cancer screening process to people with physical and mental disabilities.
Allowing women living in Low and Middle-Income countries to access early screening exam. This is one of KDOG’s priorities to elaborate an alternative to mammography for countries where it is unaffordable and where healthcare infrastructures are lacking.
Replicating the method for other types of cancer, especially the ovarian cancer.

Towards an easy and reliable cancer screening method at early stage

The acute sense of smell of the dog allows a reliable detection of cancers at early stage. A rapid detection enables the earlier starting of the patient care and a better diagnosis. The patient will benefit from a wider scope of treatments, and above all, will have more probabilities of definitive cure. Indeed, the smaller the tumor is, the lesser the spread stage of the disease and consequently, the more efficient the treatments will be. In certain cases, if cancer is detected early enough, chemotherapy is not necessary.

The material is light and the process is simple, completely indolent and noninvasive. ‘The woman will only have to bear a piece of tissue during some hours on her breast and then send it to the lab where the dogs will analyze it.’ explains Dr. Fromantin.

Dogs are never in contact with the patients. This method ensures complete safety for the patients, rapidity of the results and would contribute to the lowering of health inequalities thanks to its low cost.

Access to screening for disabled persons

This new screening method constitutes an alternative solution for physically and mentally disabled people. KDOG permits access to care for patients for whom mammography can be inadequate (requiring the patient to stand upright and immobile; being accompanied by a tutor). These difficulties of access for disabled women lead to a smaller rate of participation to screening^¹⁰, with harmful consequences for health and for equality.

In a wider perspective, this method could convince women who are recalcitrant to go to organized screening programs offering free mammography exams: they sometimes express difficulties of access (if living in isolated villages or small towns) and fears of consulting the medical staff. A lot of them also find the exam unpleasant and even painful. Debates about the overdiagnosis caused by the extension of mammography and unnecessary treatments are also reasons for half of the French 50-74 years-old women not to go for cancer screening.^¹¹

The KDOG technique enables women to do the test at home, in a comfortable environment, without any pain occurred.

Extending this method to developing countries

The KDOG method aims at being implemented abroad to allow early screening for breast cancer for women in Low and Middle Income countries. Diagnosis tools are dramatically lacking in some regions of the world where the number of cancer cases is also increasing.^¹² Preventing cancers at its earliest stages of development thanks to dogs’ olfaction would considerably ease patients care and treatment with local means. Many Low Income Countries don’t dispose of the adequate equipment for cancer screening and infrastructures dedicated to women’s hospitalization afterwards. Our goal is to anticipate these advanced stages of cancer so as to improve the patients care and eventually avoid the use of heavy technology for cure. We want to guarantee patients’ access to safe and high quality treatments after having benefitted from an efficient and reliable diagnosis.

Applicate the technique to other cancers

The KDOG team strives for the extension of this method to other types of cancers which are accessible transcutaneously, starting with the ovarian cancer. Nowadays, there is no simple and reliable way to test for ovarian cancer in women who do not have any signs or symptoms. Therefore ovarian cancer is often detected in advanced stages, which increases the risks of complications for the patient.

1 http://www.iarc.fr/en/media-centre/pr/2013/pdfs/pr223_E.pdf

2 https://www.theguardian.com/society/2016/nov/02/cancer-deaths-women-rise-warning-lancet

3 http://www.thelancet.com/series/womens-cancers

4 https://www.theguardian.com/society/2016/nov/02/cancer-deaths-women-rise-warning-lancet

5 http://www.who.int/cancer/detection/breastcancer/en/index3.html

6 http://www.iarc.fr/en/media-centre/pr/2013/pdfs/pr223_E.pdf

7 http://www.e-cancer.fr/Patients-et-proches/Les-cancers/Cancer-du-sein/Quelques-chiffres

8 http://www.e-cancer.fr/Professionnels-de-sante/Depistage-et-detection-precoce/Depistage-du-cancer-du-sein/Le-programme-de-depistage-organise

9 https://www.medicaldetectiondogs.org.uk/866-2/

10 https://www.cdc.gov/features/breastcancerscreening/index.html

11 https://www.lexpress.fr/actualite/societe/sante/cancer-du-sein-faut-il-se-mefier-de-la-mammographie_1323842.html

12 http://www.jeuneafrique.com/33734/societe/sant-10-choses-savoir-sur-le-cancer-en-afrique/

https://link.springer.com/content/pdf/10.1186/s40064-015-1394-8.pdf