Research on gynaecologiconcology in Norway

The gynaecologic cancer milieu in Norway isquite active in research, both more basic researchand clinical research.

An important prerequisite for basic research isaccess to biological material, such as tissue,blood and other material. Prospective collectionof biologic material is resource demanding butnecessary and has been done for several years. Inrecent years, we have used image material fromMRI, CT and PET as well.

“Immunotherapy has been of interest formany years but so far without any majorbreakthrough in gynecologic cancer. In recent years immune checkpoint in-hibitors have had a major breakthrough,especially in malignant melanoma. Activity has been shown also in othercancer types. The time has come to test these drugs in gynecologic cancer. Norwegian centers are participating inseveral of these studies.”

In Norway we have 4 cancer centres, with OsloUniversity Hospital being the largest followed byBergen, Trondheim and Tromsoe. Due to spacelimitations I will restrict this presentation to the2 biggest university hospitals.

At Oslo University Hospital we especially focusedour translational research on cervical and ovariancancer and gynaecological sarcoma, in additionto clinical studies.

In cervical cancer, we have performed a numberof studies to better understand the biology ofthe disease and especially relating to radiationtreatment of locally advanced tumours. Low oxygen saturation (hypoxia) in the tumour makesthe tumour more resistant to radiation, evenwhen chemotherapy is added. We have identifiedtumour genes related to hypoxia. Increased activityof these genes also makes the tumour more aggressive with a higher potential of spread toother parts of the body (metastases). We haveshown how hypoxic areas of the tumour can bevisualised on MRI pictures. Further, we haveshown a close relationship with activation of thehypoxia related genes and the hypoxia indicatorswe can visualise on MRI. This is of clinical importance, as we need to find some kind of extratreatment for the tumours with hypoxic areas.Using MRI visualisation of hypoxia would allowus to focus that extra treatment on patients withthis kind of tumour and avoid giving this addi-tional treatment to all patients. Unfortunately,we do not have any good candidate for such additional treatment, but research is ongoing.

Brachytherapy is an important part of radiotherapyfor cervical cancer. This is radiation given directlyto the neck (cervix) of the uterus. It is given insuch a way that the cervix receives a high radia-tion dose, while the dose to the intestines is low.Over the years, we have spent a lot of resourcesand research to be able to give a sufficiently highdose of radiation to all tumour tissue while spar-ing the healthy tissue surrounding the tumour.Follow up of patients after treatment to learnabout their side effects and complications and

Research on gynaecologiconcology in Norway

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relating that to treatment details is important.This was the topic of a PhD a few years ago. We are now running new studies after furtheroptimisation of the radiation technique.

In ovarian cancer, we have been running a numberof studies to learn about the biology of these tumours. One of our pathologists has done extensive studies on tumour cells from ascites (fluid accumulated in the abdominal cavity) ofpatients with advanced ovarian cancer. This hasbeen possible as we have prospectively collectedascites from such patients over many years. To-gether with studies on tumour tissue, this hasgiven great insight into tumour biology. A num-ber of genes related to response to chemotherapyand to prognosis have been identified. Also theimportance of interplay between tumour andstroma has been evaluated on tumour specimens.On blood specimens, circulating tumour DNA,MRA and microRNA can be evaluated. We havefound that some microRNA may be related totumour aggressiveness and thereby to the prognosis for the patient. It will be interesting to see, whether some of these microRNA will be predictive for different kinds of treatment, as

this may have clinical relevance. It is of greatvalue to know about genes and other factors ofimportance in response to treatment, as this canbe used in the decision about type of treatmentand can be used to guide development of newdrugs and new treatment types.

“For clinical studies, all Norwegian centers for gynaecologic oncology areworking together. The number of patientswith gynaecologic cancer is relativelylow, so to be able to perform largerclinical studies we must work together.”

In gynaecologic sarcoma, we have studied the importance of clinical and biological factors forthe outcome of patients. We are presently study-ing the importance of different types of treatment,both surgical and medical treatments.

In endometrial cancer, the research group inBergen has done a tremendous job in translationalresearch, while we in Oslo have mainly focusedon clinical studies. The clinical treatment of endometrial cancer patients has very much been

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based on convention and to a lesser extent on randomised studies. The primary treatment issurgery with removal of the uterus and adnexa.There is a risk of spread of the disease outsidethe uterus, related to clinico-pathologic factors.Removal of lymph nodes for evaluation of spreadis commonly done in patients with increased riskof spread. This is associated with some morbidityand has not been shown to increase survival. InNorway and in many other countries, we areworking on a technique to only remove one or avery few lymph nodes representing the status ofall relevant lymph nodes; the so-called sentinelnode technique. Another question is whetherremoval of lymph nodes should be done at all.Maybe the surgical procedure could be replacedby imaging and chemotherapy given to patientswith apparently normal nodes, but having a highrisk of micro metastases. Work is ongoing toperform a randomised study on this topic.

The value of adjuvant treatment after surgery is

controversial. The traditional adjuvant treatmenthas been radiation, which can reduce the frequencyof pelvic relapses, but does not increase survival.For this reason, many departments have chosento give chemotherapy instead of radiation to patients with a particularly high risk of relapse.We are in the progress of publishing the resultsof such a change in a large group of patients.

For clinical studies, all Norwegian centres forgynaecologic oncology are working together. The number of patients with gynaecologic canceris relatively low, so to be able to perform largerclinical studies we must work together. Forstudies on rare conditions with a limited numberof patients, only one or two centres participateand patients from other parts of the countrytravel to one of these centres. The governmentconsiders it of importance that all patients in the country have the possibility to participate instudies on new treatments and facilitates this bypaying for travel.

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Most clinical studies are performed as a member of the European network for clinical studies ingynaecologic cancer (ENGOT). Some studies arepurely industry driven. We do have a number ofclinical questions that could best be solved byrandomised clinical trials. Unfortunately, it is verydifficult to get funding for such academic trials.Almost all funding for clinical studies comes insome way from the industry, which naturally hasan economic perspective. A better opportunity to get funding for academic clinical trials fromgovernment or at the European level is needed.

“An important prerequisite for basic research is access to biological material,such as tissue, blood and other material.Prospective collection of biologic materialis resource demanding but needed andhas been done for several years. In recentyears, we have used image material fromMRI, CT and PET as well.”

In clinical studies, we have participated in studies on the value of blocking growth signalsfor new vessels. Tumours need nutrition andthereby blood vessels to grow. In ovarian cancerit has been shown that such treatment slowsdown the regrowth of tumours after surgery(VEGF inhibition). Such inhibition can be obtained either by IV infusions or by tablets. A study to evaluate such treatment in advancedor metastatic endometrial cancer will start soon.For patients with a partial defect in their abilityto repair DNA damage, treatment with a groupof drugs called PARP inhibitors shows promise.The drug Olaparib has recently been licensed in Europe for treatment of ovarian cancer aftersuccessful treatment with chemotherapy. The license was based on results a randomised phaseII study. We are performing a similar study onpatients with relapsed ovarian cancer and willsoon start a study on treatment after end of firstline chemotherapy.

Inhibition of signal pathways that are crucial forthe tumour is called targeted therapy. The mo-lecular biology of most cases of ovarian cancer isquite heterogeneous and so far no treatable com-mon pathway has been found. In patients withlow grade serous ovarian cancer, some importantpathways are known. We participate in a studytargeting such a pathway. This is a rare tumourgroup with few patients so only Oslo and Bergenparticipate. Patients from other regions thustravel to one of these two hospitals. Travel costsare paid by the government to allow for equalopportunity for all inhabitants in the country toparticipate in this kind of studys. In endometrialcancer some pathways are also known and clinicalstudies blocking these pathways are of interest.We are participating in such a study.

Immunotherapy has been of interest for manyyears but so far without any major breakthroughin gynaecologic cancer. In recent years immunecheckpoint inhibitors have had a major break-through, especially in malignant melanoma. Activity has been shown also in other cancertypes. The time has come to test these drugs in gynaecologic cancer. Norwegian centers areparticipating in several of these studies.

In regard of surgical studies, we have participatedin a randomised study to evaluate the benefit ofsurgery before chemotherapy for relapsed cancer.The results of that study are pending. We areawaiting the start of a study to evaluate the benefitof removing lymph nodes in endometrial cancer.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gunnar KristensenProfessor, Consultant, PhDOslo University Hospital, RadiumhospitalTel: +47 22 93 40 00gbk@ous-hf.nowww.oslo-universitetssykehus.no

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The Bergen gynaecological cancer research grouphas 23 active members focusing on clinical andmolecular aspects of gynaecological cancers. The group is embedded in Haukeland University Hospital, being a Norwegian ESGO1 accreditedtraining centre for gynaecologic oncology andthe Center of Excellence CCBIO, co-directed byProfessor Helga B Salvesen. The group has generated break throughs published in top rankedgeneral (Nature, PNAS, NEJM) and specialisedcancer journals (JCO, CR, CCR)2, and contributedto the discovery of new potential treatment targets and markers for individualising gynaecological cancer care.

Resources: A gynaecological cancer biobank withwell-annotated fresh frozen samples, blood andurine from >3000 consented patients with extensivefollow-up is applied to generate a range of inputdata using array techniques, and sequencing inparallel with functional imaging studies by fMRIand PET-CT. Candidate biomarkers are validatedin preclinical models and clinically-annotated formalin-fixed paraffin-embedded samples by immunohistochemistry and fluorescence in situhybridisation. Such additional validation cohortsinclude the international prospective multicentrestudy Molecular Markers in the Treatment of Endometrial Cancer (MoMaTEC trials).

Key clinical challenges in gynaecological cancersshow significant overlap for histological subtypesand clinical phenotypes, also recently supportedby comprehensive molecular tumour profiling.The challenge is now to translate this knowledgeinto clinically meaningful and applicable tests toimprove and individualise patient care. Our research environment is presently in a uniqueposition to take some of this new knowledge toclinical implementation studies.

The graphical abstract summarises the researchstrategy to contribute to more precision in gynaecological cancer care: By exploring primaryand metastatic lesions, in parallel with compre-hensive clinical annotation, advanced imagingand drug testing in preclinical models, we willdefine promising targets and conduct molecularlybased clinical trials. Individualised treatment andfollow-up based on biomarker-determined riskprofiles will be implemented in studies in parallel,whilst assessing quality of life and costs.

1 ESGO: European Society of Gynaecological Oncology, ENITEC: European Network of Individual Treatment in Endometrial Cancer

2 Ojesina AI …..Salvesen* and Meyerson* (*joint senior authors): Nature;2014;506:371-5; Salvesen et al. PNAS 2009; 106:4834-4839; Dutt A,Salvesen et al, PNAS 2008; 05:8713-7; Salvesen et al, JCO 1999;

17:1382-90; Hoshida Y et al. NEJM 2008;539:1995-2004

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . University of Bergen

Presentation of theBergen group

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According to World Cancer Report 2014(IARC), at least one third of cancers are preventable. This is true for gynaecological cancers, especially cervical cancer. However, lessthan 5% of the whole cancer control budget inthe EU is spared for prevention. A great majorityof the total budget is still spent on treatment ofcancer and only 25 of the 28 EU member stateshave a strategic cancer control plan.

Based on the UN General Assembly Resolutionin 2011, cancer control and prevention will bethe main focus for all countries within the nextdecade. New data estimates that the $18bn increase in funding per year by the internationalcommunity could result in a 30% reduction incancer deaths in low and middle-income countriesby 2030.

In this respect scientific and non-scientific societies including ESGO have initiated newawareness campaigns. ESGO is the principal European society of gynaecological oncologycontributing to the study, prevention and treatment of gynecological cancer which also organises state of the art symposiums to upgradethe knowledge and skills about the highlightedtopics, via the world’s most famous experts. Inorder to lead in several gynaecological cancersprevention, ESGO has decided to organise a2016 symposium focusing on the prevention ofgynaecological cancers, with specialised lectureson primary, secondary and tertiary prevention ofcervical, endometrial, breast and ovarian cancers.In addition to the up to date scientific reviews,this meeting will also give an opportunity toreach and train all relevant groups such as cancer

Murat Gultekin, Vice-President of the European Society of Gynaecological Oncology (ESGO) highlights the importance of early detection of gynaecological cancers for prevention…

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Gynaecological cancers – prevention and early detection

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patients, their relatives and the young generationof European doctors. With almost 30 worldwidefamous scientists, lecturers and 500 attendees fromall around Europe and the Middle East Region,the 2016 ESGO State of Art Symposium-Antalya/Turkey will be a trademark and a cornerstone ongynecological cancer prevention strategies.

Cervical CancerCervical cancer is the 4th most common cancerof women around the world. Although it is apreventable, 2 women every 1 hour in the European Union, currently lose their lives because of this type of cancer.

HPV is the main causative agent of cervical cancers and more than 70% of these cancers arerelated to HPV type 16 and 18. This is importantbecause it means that a great majority of thesecancers can be prevented via HPV vaccinationand cancer related deaths can be avoided by earlydiagnosis through screening.

HPV VaccinationCervical cancer can be prevented and this canbegin from childhood. We can save our children’slives by vaccinating our children and avoid atleast 3 out of 4 deaths by an effective HPV vac-cination. These vaccinations are FDA approved,

effective and safe vaccines, against to knownoncogenic HPV types. Unlike most other vaccines,which are administered to children under theage of 5, HPV vaccines are inoculated to girlsaged 9 to 13.

In contrast with the fact that HPV vaccines canprevent every 4 of 5 deaths from the cervicalcancer and don’t have serious side effects, vaccination rates are still low around the world.According to VAERS (Vaccine Adverse EventReporting System) about 92% of the side effectreports were classified as non-serious. The mostcommon side effects are; injection problems,fever, headache, nausea and muscle or joint pain.Despite speculations the vaccine was found tonot have any relation to a risk of multiple sclerosisin many scientific studies.

ScreeningBesides prevention, early detection by screeningstill remains important. Population based, effective and well-designed screening programsshould be the goal of achievement for all countriesin a view of public health. In addition to the ongoing cytology programs, countries have manydifferent screening strategies such as VIA/ VILI/HPV DNA or a combination of all. Recent evi-dence shows HPV DNA can be safely used alone

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for cervical cancer, with its high scientific valueand scientifically proven success.

Uterine CancerThe most common type of uterine corpus canceris endometrial cancer, which is the 5th mostcommon cancer of women in the world. It ismostly symptomatic and could be easily diagnosedand totally curable at early stages. It is generallyseen after the menopause with only 5% of thecases under 40 years of age. Most of these cancersare related to obesity and high estrogen exposure.There aren’t any feasible and acceptable screeningmethods for endometrial cancer, however it isimportant to be aware of the fact that any post-menopausal bleeding may be an early sign of it.

Ovarian CancerOvarian cancer is the 7th most common canceramong women in the world and it is the mostdeadly gynecologic cancer. Although there arenot any adoptable screening methods for thiscancer at a community level, it is curable if diagnosed in the early stages. It is important toraise public awareness about the symptoms ofovarian cancer so it can be detected earlier.There is also a genetic proportion of this cancerbut only 10% of ovarian cancer cases have thisliability. Women who have a family history of

ovarian, endometrial or colorectal cancer could bescreened for genetic predisposition and be pre-vented by some measures. There are many studieson ovarian cancer which may lead screening andearly diagnosis or new treatment options.

ConclusionMore than 70% of gynecological cancers can be prevented and the harm caused by them canbe reduced by several measures such as screeningand vaccination programs. It is important to beaware of first the importance of prevention thenthe importance of early diagnosis.

In conclusion; “Raising Awareness” should be ourfirst as this is the most important initial point forsaving more people’s life.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Murat Gultekin, MD, Assoc. ProfessorVice-President – ESGOIARC Governing Council Member

Director Cancer Control DepartmentTurkish Ministry of Healthwww.esgo.org

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Oslo University Hospital RadiumhospitalTel: +47 22 93 40 00www.oslo-universitetssykehus.no