3 oktober 2018: Bron: Annals of Internal Medicine

Wat veel mensen niet weten en ook oncologen daar zelden op onderzoeken is dat soms kankerpatienten tumoren hebben in verschillende organen met een andere expressie/DNA profiel. Ook wel 'multiple primary tumours' genoemd. In Azië wordt daar veel meer aandacht aan besteed al bij de eerste diagnose. Vooral bij vormen van kanker in de buikholte en bekkengebied en dan vooral bij vrouwen komen verschillende vormen van primaire kanker voor zelfs binnen 1 tumor. Maar met de voortschrijdende technieken zullen verschillen tussen primaire tumoren veel vaker worden gezien. Op dit moment liggen de percentages  van 1 tot 20 procent, maar zal alleen maar meer worden. Blijkt uit een reviewstudie:

Multiple primary tumours: challenges and approaches, a review (abstract daarvan en referentielijst staat onderaan dit artikel

Hier een voorbeeld van een case studie van een vrouw van 55 jaar die primaire darmkanker had met ook tumoren in baarmoeder, galwegen/lever en maag die echter een verschillende expressie en mutatiepatroon vertoonden. Wel gemeenschappelijk was een bepaalde mutatie MLH1 die duidt op het Lynch Syndroom, soms voorkomend bij darmkanker.

Nadat de vrouw met dus vergevorderde uitgezaaide darmkanker en na verschillende chemokuren enz. alleen maar pembrolizumab kreeg toegediend via infuus kwam zij alsnog in een complete remissie. Geen tumoren meer in de darmen, geen symptomen van kanker meer in andere organen.  En is dat nu al ruim anderhalf jaar.

A single checkpoint inhibitor can be used to successfully treat two simultaneous types of primary cancer in a patient with Lynch syndrome, according to a research letter published online Sept. 25 in the Annals of Internal Medicine

Uit het abstract geciteerd en vertaald:

Benjamin Musher, M.D., en Ahmad Rahal, MD, van het Baylor College of Medicine in Houston, presenteren een case studie van een 55-jarige vrouw met uitgebreide gastro-intestinale kanker die een familiegeschiedenis had van darmkanker, baarmoederkanker en maagkanker. Een mucosale laesie van 5 cm in de bovenste dikke darm werd ontdekt in een colonoscopie, en verschillende extra levertumoren werden geïdentificeerd en bevestigd als zijnde een primair intrahepatisch galwegencarcinoom in plaats van een darmkanker uitzaaiing.
De onderzoekers identificeerden daarbij een opgetreden mutatie in MLH1, wat bevestigde dat beide soorten kanker werden veroorzaakt door het Lynch-syndroom.

De patiënt verkoos om de behandeling met een checkpointremmer (anti-PD medicijn) te starten en begon met intraveneus pembrolizumab. Een snelle en positieve reactie op de therapie werd waargenomen voor de tumoren. De darmkanker werd niet langer waargenomen tijdens  een colonoscopie op 16 maanden na de start met pembrolizumab; er werd geen hypermetabolische activiteit gezien in een PETscan in eerder aangetaste plaatsen in het lichaam van de vrouw. En er werden geen kankergerelateerde symptomen meer gezien na 18 maanden therapie.

Het studierapport van de studie: Single-Agent Immunotherapy for Two Types of Cancer in One Patient is tegen betaling in te zien.

Een ander studierapprot relevant in dit opzicht is deze studie: Multiple primary tumours: challenges and approaches, a review(abstract daarvan en referentielijst staat onderaan dit artikel

The risk of developing a second primary malignancy is varying in different cancer sites and is reported in a range from 1% (primary liver malignancy) up to 16% (primary bladder cancer). Weir et al found an incidence of multiple primaries of 19.7% following the SEER guidelines (or 16.9% IACR rules) in colon and 21% (SEER; 19.9% IACR) in patients with lung cancer. Amer et al found similar incidences of multiple primaries in patients with colon cancer; however, they only reported 5.6% multiple primaries in patients with lung cancer.

Hieronder een grafiek van veel voorkomende multiple primary tumours gerelateerd aan erfelijke vormen van kanker. Maar in genomde studie staat veel meer en beschreven per kankervorm:

Table 4

Clinical scenarios and potential genetic cancer syndrome

Clinical picture, patient with a history or diagnosis of (synchronous or metachronous) Familial cancer syndrome to think of Full picture of familial cancer syndrome
Synchronous bilateral breast cancer or secondary (metachronous) breast cancer Hereditary breast and ovarian cancer (HBOC) [BRCA1, BRCA2] •Breast cancer
•Ovarian cancer
Breast and ovarian cancers HBOC [BRCA 1/2] •Male breast cancer
Prostate cancer and pancreatic cancer or melanoma HBOC [BRCA 2] •Prostate cancer
•Melanoma
(Multiple) renal cell carcinomas VHL •Renal cell carcinoma <47 years
Renal cell carcinoma and pancreatic cystic lesions VHL •Multiple renal cysts
Haemangioblastomas of central nervous system (CNS) and retina VHL •Multiple pancreas cysts and pancreatic neuroendocrine tumour
•CNS and retinal haemagioblastomas
•Phaeochromocytomas
•Endolymphatic sac tumours
•Cystadenomas of epididymis or broad ligament
Breast cancer and sarcoma Li-Fraumeni syndrome •Soft tissue sarcoma and osteosarcoma
Breast cancer and leukaemia Li-Fraumeni syndrome •Premenopausal breast cancer
•Leukaemia
•Brain tumours
•Adrenocortical carcinoma
•Lung bronchoalveolar cancer
Colon and endometrial cancers Lynch syndrome •Colon cancer
Colon and ovarian cancers HNPCC •Endometrial cancer
•Ovarian cancer
•Renal pelvis cancers
•Ureteral cancers
•Pancreatic and hepatobiliary cancers
•Stomach and small bowel cancers
Multiple colon polpys and/or colon cancer Familial adenomatous polyposis •Colon cancer
•Duodenal cancer
•Thyroid cancer
•Hepatoblastoma
Parathyroid adenomas and pituitary adenomas MEN1 •Pituitary tumours
•Parathyroid tumours
•Endocrine tumours of the gastro–entero–pancreatic tract
•Carcinoid tumours
Medullary thyroid cancer and phaeochromocytoma MEN 2 •Medullary thyroid cancer
•Phaeochromocytoma
•Parathyroid hyperplasia/adenoma

HNPCC, hereditary non-polyposis colon cancer; MEN1, multiple endocrine neoplasia type 1; MEN2, multiple endocrine neoplasia type 2; VHL, von Hippel-Lindau.

Hier het abstract van de case studie en daaronder die van de multiple primary studies:

A single checkpoint inhibitor can be used to successfully treat two simultaneous types of primary cancer in a patient with Lynch syndrome

Single-Agent Immunotherapy for Two Types of Cancer in One Patient

Benjamin Musher, MD; Ahmad Rahal, MD

Background: Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer) is characterized by an inability to recognize and repair some errors that develop during DNA replication. This defect in mismatch repair is an autosomal dominant disorder that increases risk for several types of cancer, including colorectal, uterine, gastric, pancreatic, ovarian, and bile duct.

Objective: To show that a single immunotherapeutic agent can successfully treat more than 1 type of cancer in the same patient when the cancer has a common genetic cause.

Case Report: We evaluated a 55-year-old woman with extensive gastrointestinal cancer. The patient had a family history of colon, uterine, and gastric cancer and presented with abdominal pain, fatigue, and weight loss. Colonoscopy revealed a 5-cm mucosal lesion in the ascending colon (Figure 1, left) confirmed by biopsy to be adenocarcinoma of colonic origin. Staging positron emission tomography–computed tomography showed hypermetabolism in the ascending colon mass and additional tracer uptake in a 12-cm mass in the right hepatic lobe; several additional liver masses; and bulky portohepatic, para-aortic, and mediastinal nodes (Figure 2, left). Liver biopsy was performed, and immunohistochemical staining of a biopsy specimen was positive for CK7/CK17 and negative for CK20/CDX-2, confirming primary intrahepatic cholangiocarcinoma rather than colon cancer metastasis. Additional staining of the specimen for proteins that repair mismatched DNA showed an absence of MLH1 expression. Sequencing the patient's DNA revealed a deleterious mutation in MLH1, which confirmed that Lynch syndrome caused both types of cancer.

Based on a combination of factors (diagnosis, treatment, demographics), it is expected that in the course of the coming years, the prevalence of patients with multiple primaries will increase. In the literature, depending on definition, the frequency of multiple primaries ranges between 2.4% and 17% and it is important to realise that with longer follow-up the number of multiple primaries increases in all studies significantly and also that most of the epidemiological studies are based on data acquired more than 10 years ago and that therefore with longer follow-up or in subsequent studies the percentage of patients with synchronous but mainly metachronous multiple primaries will increase.

. 2017; 2(2): e000172.
Published online 2017 May 2. doi:  10.1136/esmoopen-2017-000172
PMCID: PMC5519797
PMID: 28761745

Multiple primary tumours: challenges and approaches, a review

Abstract

When in a patient more than one tumour in the same or a different organ is diagnosed, multiple primary tumours may be present. For epidemiological studies, different definitions of multiple primaries are used with the two main definitions coming from the project Surveillance Epidemiology and End Results and the International Association of Cancer Registries and International Agency for Research on Cancer. The differences in the two definitions have to be taken into consideration when reports on multiple primaries are analysed. In this review, the literature on multiple primaries is reviewed and summarised. Overall, the frequency of multiple primaries is reported in the range of 2–17%.

Aetiological factors that may predispose patients to multiple primaries can be grouped into host related, lifestyle factors and environmental influences. Some of the most common cancer predisposition syndromes based on a clinical presentation are discussed and the relevant genetic evaluation and testing are characterised.

Importantly, from a clinical standpoint, clinical situations when multiple primaries should be suspected and ruled out in a patient are discussed.

Furthermore, general principles and possible treatment strategies for patients with synchronous and metachronous multiple primary tumours are highlighted.

Discussion and conclusion

Based on a combination of factors (diagnosis, treatment, demographics), it is expected that in the course of the coming years, the prevalence of patients with multiple primaries will increase. In the literature, depending on definition, the frequency of multiple primaries ranges between 2.4% and 17% and it is important to realise that with longer follow-up the number of multiple primaries increases in all studies significantly and also that most of the epidemiological studies are based on data acquired more than 10 years ago and that therefore with longer follow-up or in subsequent studies the percentage of patients with synchronous but mainly metachronous multiple primaries will increase.

Also, it is important to recognise that certain patient populations are at higher risk of developing multiple primaries, namely male patients and patients with a history of smoking or alcoholism but also patients diagnosed with a primary malignancy at an early stage and lower grade and patients with a hereditary cancer syndrome. Also, the number of octogenarians diagnosed with cancer is increasing and at the same time the frequency of multiple primaries in older patients who are potentially fit enough to receive active antineoplastic therapy.

Treatment-related secondary malignancies as observed in patients with germ cell or Hodgkin’s lymphoma are well characterised but with novel targeted therapies it is currently unclear whether an increased rate of secondary malignancies needs to be taken into consideration. For the B-RAF (rapidly accelerated fibrosarcoma) inhibitor vemurafenib, an increased rate of secondary cutaneous malignancies was demonstrated and requires careful and regular dermatological evaluation for patients on treatment. Also, for the PARP inhibitor olaparib, cases of myelodysplastic syndromes and AML have been observed and careful monitoring of patients for haematological toxicity is recommended.

With the advances and wider availability of genetic testing (eg, gene panels), patients diagnosed with multiple primaries will be increasingly investigated for an underlying cancer predisposition. The gain of knowledge on patients with hereditary cancer and cancer survivors will hopefully allow the development of specific management and surveillance measures.

For clinical trials, generally patients with secondary malignancies are very often excluded unless they have been low grade/stage and were successfully treated at least 3-5 years ago. To reflect more of a real life population and to enable patients with a prior cancer history participation in clinical trials, the exclusion criteria, especially for early phase clinical trials could be modified to only exclude patients who currently require active anticancer therapy. Admittedly, this may add marked complexity in assessing efficacy and progression and may therefore not be suitable for phase III clinical trials.

Further research is needed, especially with regards to the areas of the treatment of patients with synchronous or metachronous multiple primary cancers. Also, the impact of prior therapies on prognosis, antitumour efficacy and toxicity needs to be better characterised.

Footnotes

Contributors: We confirm that all co-authors have contributed to the generation of the manuscript.

Competing interests: AO: advisory role (compensated, institutional): Astellas, Bayer, Sanofi, Roche, Janssen. Research support (institutional): Teva, Janssen. Travel support: Astellas, Bayer, Sanofi, Roche. SS: advisory role (compensated institutional): Böhringer Ingelheim, BMS. AV, KH, HF, CH and TC report no competing interests.

Provenance and peer review: Commissioned; externally peer reviewed.

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