Survivorship is an increasingly important component of cancer care

A cancer survivor is defined as anyone who is living with cancer, or whose cancer has gone into remission. Traditionally cancer care has concentrated on diagnosing and treating the disease, and comparatively little support has been given to patients once their disease has been cured.

Survivorship care plans include educating patients about the potential long-term effects of their treatment; designing an appropriate follow up plan to monitor patients for new and recurrent tumours; and providing patients with necessary psychological and social support to allow them to return to their normal lives (Hewitt et al., 2005). However, this is a new area of research and there is currently little evidence about what information patients are given, and the impact of cancer on patients’ lives to inform survivorship guidelines.

In order to assess what information kidney cancer patients received during their treatment, and the physical, psychological and emotional impact of having kidney cancer, Kidney Cancer Canada conducted an online survey (Moretto et al., 2014). Two multiple choice questionnaires were designed – one for patients and their care givers, and one for urologists, and a total of 361 surveys were returned; 276 by patients, 45 by care givers and 40 by urologists.

The surveys showed that there were some major differences between what urologists reported telling their patients, and what information patients remember receiving. Over 80% of urologists reported advising patients to maintain adequate blood pressure control, stop smoking and follow a healthy lifestyle, while under 40% of patients remember receiving this advice. Furthermore, again over 80% of urologists report giving patients specific information about their patients’ tumour characteristics, lymph node involvement, and post-operative renal function, fewer than 60% of patients remember getting this information. However, similar numbers of urologists and patients report discussing tumour size and treatment options.

The reason for this difference is not clear. One explanation is that although doctors give this advice, patient retention is low as they may be in shock after receiving a cancer diagnosis. Alternatively, it could be a block in communication where doctors do give this information, but in a way that patients are not able to fully understand. There is also a chance that there is some recall bias in these results, as some patients had been diagnosed more than three years before they took the survey, and doctors may have reported what information they would like to give patients when not under time constraints, rather than what information they actually give patients in a pressured clinic environment.

Another interesting result highlighted by the survey is that although doctors accurately predicted the emotional impact of issues directly related to patients’ cancer diagnosis – such as fear of cancer recurrence – they consistently underestimated the number of patients who would suffer depression and related symptoms following a cancer diagnosis.

These results suggest that the way information is given to kidney cancer survivors needs to be assessed, and that patients need to be given more emotional support to come to terms with being a cancer survivor. Indeed, there are a number of groups working to improve the support given to cancer survivors: the Kidney Cancer Research Network of Canada Survivorship Initiative; the National Cancer Survivorship Initiative in the UK; and the LIVESTRONG Care Plan in the US.

It is estimated that there are 2 million cancer survivors in the UK, and 12 million in the US. As diagnosis rates and treatments improve, survivorship will be an increasingly crucial part of the cancer care pathway, and access to survivorship support services is one of the rights set out in the European Cancer Patient’s Bill of Rights. As well as a moral imperative to ensure the health and wellbeing of cancer survivors, with the annual global cost of disability and early death due to cancer approaching $1 trillion USD, there is also an economic benefit to ensure that cancer survivors have the support they need to live full, healthy and productive lives following their illness.

 

  • Hewitt M, Greenfield S, Stovall, E (2005). From Cancer Patient to Cancer Survivor: Lost in Translation. National Academies Press, Institute of Medicine Consensus Report
  • Moretto P, Jewett MA, Basiuk J, Maskens D, & Canil CM (2014). Kidney cancer survivorship survey of urologists and survivors: The gap in perceptions of care, but agreement on needs. Canadian Urological Association journal = Journal de l’Association des urologues du Canada, 8 (5-6), 190-4 PMID: 25024789

 www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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FLCN modulates autophagy via its interactions with GABARAP and ULK1

A number of studies have suggested that FLCN regulates autophagy, although precisely how was unknown. A recent study by Dr Elaine Dunlop and Dr Andy Tee from Cardiff University report that FLCN regulates autophagy through interactions with GABARAP and ULK1.

Dunlop et al. (2014) first analysed whether autophagy was dysregulated in FLCN-deficient HK2 and MEF cells. They found that although acute starvation-induced autophagy was unperturbed, basal autophagic flux was reduced in these cells, as measured by increased SQSTM1 expression and impaired autophagosome maturation.

As FNIP1 has been previously shown to interact with the autophagy protein GABARAP (Behrends et al., 2010), Dunlop et al. investigated whether FLCN regulated autophagy through GABARAP. Mass spectrometry identified eight high-confidence interacting partners for GABARAP, including both FLCN and FNIP1. Further in vitro experiments confirmed this interaction, and showed that FLCN was only able to bind GABARAP in the presence of FNIP1 or FNIP2, and that FNIP2 in particular potentiated this interaction.

ULK1, a key activator of autophagy, was found to control the FLCN-FNIP-GABARAP interaction by phosphorylating three novel sites in the FLCN protein – S406, S537 and S542. However, ULK1 was still able to dissociate a FLCN-FNIP-GABARAP complex containing a triple serine-to-alanine unphosphorylateable FLCN mutant, suggesting that ULK1 targets additional sites in FLCN, the FNIPs or GABARAP.

Analysis of a BHD patient’s renal tumour showed elevated levels of SQSTM1, GABARAP and MAP1LC3B expression, suggesting autophagy was impaired in the tumour. Furthermore, mutant FLCN proteins derived from BHD-patient mutations interacted preferentially with ULK1 than GABARAP, and did not activate autophagy when the C-terminal domain was truncated. This suggests that the C-terminal end of the protein is important in order to dissociate from ULK1, interact with GABARAP and to ultimately activate autophagy.

These results suggest that FLCN binding to GABARAP is required for basal autophagy to proceed, and that ULK1 usually acts to inhibit the FLCN-FNIP-GABARAP complex. During nutrient sufficiency, ULK1 is inactivated by mTOR signalling, suggesting that the FLCN-FNIP-GABARAP complex is able stimulate basal autophagy, which is commonly activated during cell growth (Musiwaro et al., 2013). Conversely, during starvation conditions, AMPK activates ULK1 which, in turn, inhibits the FLCN-FNIP-GABARAP complex, thus concomitantly inhibiting basal autophagy and activating starvation-induced autophagy.

FLCN has been shown to regulate mTOR signalling and AMPK signalling, both of which function upstream of ULK1, and to affect MAP1LC3B and MAP1LC3C expression (Bastola et al., 2013), indicating that FLCN may control autophagy at multiple points in the pathway. Furthermore, FLCN has been shown to activate, inhibit, or have no effect on autophagy in different cell types, indicating that FLCN’s role in autophagy – like its role in other signalling pathways – is highly cell type specific. Indeed, as FNIP2 and FNIP1 were both required for the FLCN-GABARAP interaction in this study, it is likely that differential expression of FLCN’s interacting proteins modifies FLCN’s function in the cell.

However, dysregulated autophagy is a common feature of many kidney cancers, and the results of this study suggest that reduced autophagy may drive renal tumorigenesis in BHD. This lends further support to earlier reports that radiotherapy and Paclitaxel chemotherapy, both of which stimulate autophagy, may prove effective treatments for BHD-associated kidney cancer.

 

  • Bastola P, Stratton Y, Kellner E, Mikhaylova O, Yi Y, Sartor MA, Medvedovic M, Biesiada J, Meller J, & Czyzyk-Krzeska MF (2013). Folliculin contributes to VHL tumor suppressing activity in renal cancer through regulation of autophagy. PloS one, 8 (7) PMID: 23922894
  • Behrends C, Sowa ME, Gygi SP, & Harper JW (2010). Network organization of the human autophagy system. Nature, 466 (7302), 68-76 PMID: 20562859
  • Dunlop EA, Seifan S, Claessens T, Behrends C, Kamps MA, Rozycka E, Kemp AJ, Nookala RK, Blenis J, Coull BJ, Murray JT, van Steensel MA, Wilkinson S, & Tee AR (2014). FLCN, a novel autophagy component, interacts with GABARAP and is regulated by ULK1 phosphorylation. Autophagy, 10 (10) PMID: 25126726
  • Musiwaro P, Smith M, Manifava M, Walker SA, & Ktistakis NT (2013). Characteristics and requirements of basal autophagy in HEK 293 cells. Autophagy, 9 (9), 1407-17 PMID: 23800949

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

pf button FLCN modulates autophagy via its interactions with GABARAP and ULK1

Folliculin function is highly cell-specific

Whilst trying to elucidate the role of FLCN, a number of studies have reported opposing results. FLCN has been shown to both activate and inhibit mTOR signalling, AMPK signalling and RhoA signalling and to both potentiate and abrogate cell-cell adhesion. It is thought that this may be due to cell type or context-specific factors (Hudon et al., 2010). A new study from Professor Lisa Henske’s team at Harvard Medical School in Boston, USA, has shown that FLCN depletion leads to highly cell specific defects.

In order to investigate how loss of FLCN leads to cystogenesis in the lung, Khabibullin et al. (2014) used siRNAs to downregulate FLCN expression in human bronchial epithelial (HBE) cells, and small airways epithelial cells (SAECs). A reduction of FLCN expression in HBE cells led to reduced AMPK signalling and MAPK signalling, increased TGF-β signalling and cell-cell adhesion, and had no effect on mTOR signalling. Conversely, reduced FLCN expression in SAECs led to increased mTOR signalling, decreased TGF-B signalling and had no effect on AMPK signalling, MAPK signalling, or cell-cell adhesion.

Autophagy, Cofilin phosphorylation, Cox4 expression, and cell doubling remained unaffected, and FLCN expression was predominantly cytoplasmic in both cell lines. These results contrast with those from other studies which show that FLCN stimulates or inhibits autophagy in a variety of cell types (Bastola et al., 2013, Hasumi et al., 2014, Possik et al., 2014); regulates Cofilin phosphorylation in UOK-257 cells (Lu et al., 2014); upregulates Cox4 expression in BHD-associated kidney tumours (Hasumi et al., 2012); delays cell cycle progression in UOK-257 cells (Laviolette et al., 2013); and is localised to the nucleus in UOK-257 cells (Laviolette et al., 2013).

Khabibullin et al. hypothesised that the increased cell-cell adhesion seen in HBE cells may be the underlying cause of lung cyst development, as it may make lung tissue more inflexible and reduce its ability to withstand mechanical forces caused by breathing.

To investigate this hypothesis, the authors analysed whether mice heterozygous for a FLCN deletion developed cystic airspace enlargement either spontaneously or following mechanically induced pulmonary stress (barotrauma). FLCN+/- mice did show a trend towards increased lung elastance following barotrauma, suggesting that the lungs of these mice did not respond to mechanical pressures in the same way as wildtype mice. This lends further support to previous observations that the loss of FLCN causes alveolar walls to become vulnerable to mechanical stress, which causes lung cysts to form (Goncharova et al., 2014, Kumasaka et al., 2013).

Taken together, these studies suggest that FLCN-deletion is likely to cause BHD symptoms through very different mechanisms. Indeed, biallelic FLCN inactivation is required for renal tumourigenesis (Vocke et al., 2005), while FLCN haploinsufficiency appears to cause the skin and lung symptoms of BHD. Thus, it is possible that separate treatments will have to be developed for each BHD symptom. Furthermore, due to the opposing effects of FLCN loss in different cell types, it is possible that the therapy for one symptom may exacerbate another symptom, meaning that therapies may need to be specifically delivered to each organ rather than taken systemically.

 

  • Bastola P, Stratton Y, Kellner E, Mikhaylova O, Yi Y, Sartor MA, Medvedovic M, Biesiada J, Meller J, & Czyzyk-Krzeska MF (2013). Folliculin contributes to VHL tumor suppressing activity in renal cancer through regulation of autophagy. PloS one, 8 (7) PMID: 23922894
  • Goncharova EA, Goncharov DA, James ML, Atochina-Vasserman EN, Stepanova V, Hong SB, Li H, Gonzales L, Baba M, Linehan WM, Gow AJ, Margulies S, Guttentag S, Schmidt LS, & Krymskaya VP (2014). Folliculin controls lung alveolar enlargement and epithelial cell survival through E-cadherin, LKB1, and AMPK. Cell reports, 7 (2), 412-23 PMID: 24726356
  • Hasumi H, Baba M, Hasumi Y, Huang Y, Oh H, Hughes RM, Klein ME, Takikita S, Nagashima K, Schmidt LS, & Linehan WM (2012). Regulation of mitochondrial oxidative metabolism by tumor suppressor FLCN. Journal of the National Cancer Institute, 104 (22), 1750-64 PMID: 23150719
  • Hasumi Y, Baba M, Hasumi H, Huang Y, Lang M, Reindorf R, Oh HB, Sciarretta S, Nagashima K, Haines DC, Schneider MD, Adelstein RS, Schmidt LS, Sadoshima J, & Marston Linehan W (2014). Folliculin (Flcn) inactivation leads to murine cardiac hypertrophy through mTORC1 deregulation. Human molecular genetics PMID: 24908670
  • Hudon V, Sabourin S, Dydensborg AB, Kottis V, Ghazi A, Paquet M, Crosby K, Pomerleau V, Uetani N, & Pause A (2010). Renal tumour suppressor function of the Birt-Hogg-Dubé syndrome gene product folliculin. Journal of medical genetics, 47 (3), 182-9 PMID: 19843504
  • Khabibullin D, Medvetz DA, Pinilla M, Hariharan V, Li C, Hergrueter A, Laucho Contreras M, Zhang E, Parkhitko A, Yu JJ, Owen CA, Huang H, Baron RM, & Henske EP (2014). Folliculin regulates cell-cell adhesion, AMPK, and mTORC1 in a cell-type-specific manner in lung-derived cells. Physiological reports, 2 (8) PMID: 25121506
  • Kumasaka T, Hayashi T, Mitani K, Kataoka H, Kikkawa M, Tobino K, Kobayashi E, Gunji Y, Kunogi M, Kurihara M, & Seyama K (2014). Characterization of pulmonary cysts in Birt-Hogg-Dubé syndrome: histopathological and morphometric analysis of 229 pulmonary cysts from 50 unrelated patients. Histopathology, 65 (1), 100-10 PMID: 24393238
  • Laviolette LA, Wilson J, Koller J, Neil C, Hulick P, Rejtar T, Karger B, Teh BT, & Iliopoulos O (2013). Human folliculin delays cell cycle progression through late S and G2/M-phases: effect of phosphorylation and tumor associated mutations. PloS one, 8 (7) PMID: 23874397
  • Lu X, Boora U, Seabra L, Rabai EM, Fenton J, Reiman A, Nagy Z, & Maher ER (2014). Knockdown of Slingshot 2 (SSH2) serine phosphatase induces Caspase3 activation in human carcinoma cell lines with the loss of the Birt-Hogg-Dubé tumour suppressor gene (FLCN). Oncogene, 33 (8), 956-65 PMID: 23416984
  • Possik E, Jalali Z, Nouët Y, Yan M, Gingras MC, Schmeisser K, Panaite L, Dupuy F, Kharitidi D, Chotard L, Jones RG, Hall DH, & Pause A (2014). Folliculin regulates ampk-dependent autophagy and metabolic stress survival. PLoS genetics, 10 (4) PMID: 24763318
  • Vocke CD, Yang Y, Pavlovich CP, Schmidt LS, Nickerson ML, Torres-Cabala CA, Merino MJ, Walther MM, Zbar B, & Linehan WM (2005). High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dubé-associated renal tumors. Journal of the National Cancer Institute, 97 (12), 931-5 PMID: 15956655

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

pf button Folliculin function is highly cell specific

Finding useful biomarkers to predict efficacy of Sunitinib

Biological markers – or biomarkers – are an area of extreme interest in medicine, as they can be used to diagnose illness, predict the likely course of a disease, or to predict patients’ response to a particular intervention. Diagnostic, prognostic, and predictive biomarkers can be any biological material, such as DNA, RNA, proteins or metabolites.

In order to be useful, biomarkers need to be easily quantifiable, and their presence or absence needs to be highly associated with a biological state or outcome. For example, a commonly used diagnostic biomarker is prostate specific antigen (PSA), which allows prostate health to be inferred from a simple blood test.

There are currently eight FDA-approved systemic treatments available to treat metastatic renal cancers, and more are being developed. However, patients do not respond equally well to the different treatments. Thus finding biomarkers to accurately predict which patients will benefit from which treatment will improve the prognosis for patients with advanced kidney cancer.

A recent study by Motzer et al. (2014) investigated a number of potential biomarkers to predict the efficiacy of the tyrosine kinase inhibitor Sunitinib, a commonly used first line therapy for metastatic renal cancer. This study was performed as part of the Renal EFFECT Trial testing the efficacy of Sunitinib administered on 4/2 schedule of 50 mg/day for 4 weeks, followed by a two week rest period, versus a continuous dosage schedule of 37.5 mg/day. 292 patients were enrolled in this study and continued treatment for up to two years.

Motzer et al. investigated several previously reported biomarkers linked to tyrosine kinase inhibitor efficacy – single nucleotide polymorphisms (SNPs) in VEGF-A and VEGFR3 (Garcia-Donas et al., 2011, Schneider et al., 2008), HIF1α and CA-IX expression in tumours (Dornbusch et al., 2013, Muriel Lopez et al., 2012), and VHL gene inactivation by mutation, gene deletion or promoter methylation (Moore et al., 2011) – and analysed the levels of serum soluble proteins in patients’ blood before and after treatment.

No statistically significant link was observed between the tumour response to treatment and the VEGF-A or VEGFR3 SNPs analysed, or CA-IX tumour expression. Lower HIF1α tumour expression and VHL inactivation was associated with increased time to tumour progression and progression free survival was observed in the patients receiving Sunitinib on the 4/2 schedule, but not the continuous dosing schedule. Finally, low ANG2 and high MMP2 levels in blood serum before treatment were both associated with increased tumour response to Sunitinib treatment.

Defining a set of biomarkers for all systemic kidney cancer therapies will allow clinicians to choose the best drug for each patient. Furthermore, the fact that HIF1α expression and VHL gene inactivation only correlated with outcomes for patients on the 4/2 dosage schedule suggests that biomarkers may also indicate the optimal dosage schedule, thus allowing a personalised medicine approach for patients with advanced kidney cancer. However, this study did not replicate earlier findings linking CA-IX tumour expression, VEGF-A SNPs and VEGFR3 SNPs to treatment response, suggesting that finding reliable biomarkers will be a difficult undertaking and that multiple biomarkers will be required in order to accurately predict treatment efficacy.

  • Dornbusch J, Zacharis A, Meinhardt M, Erdmann K, Wolff I, Froehner M, Wirth MP, Zastrow S, & Fuessel S (2013). Analyses of potential predictive markers and survival data for a response to sunitinib in patients with metastatic renal cell carcinoma. PloS one, 8 (9) PMID: 24086736
  • Garcia-Donas J, Esteban E, Leandro-García LJ, Castellano DE, del Alba AG, Climent MA, Arranz JA, Gallardo E, Puente J, Bellmunt J, Mellado B, Martínez E, Moreno F, Font A, Robledo M, & Rodríguez-Antona C (2011). Single nucleotide polymorphism associations with response and toxic effects in patients with advanced renal-cell carcinoma treated with first-line sunitinib: a multicentre, observational, prospective study. The Lancet. Oncology, 12 (12), 1143-50 PMID: 22015057
  • Moore LE, Nickerson ML, Brennan P, Toro JR, Jaeger E, Rinsky J, Han SS, Zaridze D, Matveev V, Janout V, Kollarova H, Bencko V, Navratilova M, Szeszenia-Dabrowska N, Mates D, Schmidt LS, Lenz P, Karami S, Linehan WM, Merino M, Chanock S, Boffetta P, Chow WH, Waldman FM, & Rothman N (2011). Von Hippel-Lindau (VHL) inactivation in sporadic clear cell renal cancer: associations with germline VHL polymorphisms and etiologic risk factors. PLoS genetics, 7 (10) PMID: 22022277
  • Motzer et al., PMID: 25100134
  • Muriel López C, Esteban E, Astudillo A, Pardo P, Berros JP, Izquierdo M, Crespo G, Fonseca PJ, Sanmamed M, & Martínez-Camblor P (2012). Predictive factors for response to treatment in patients with advanced renal cell carcinoma. Investigational new drugs, 30 (6), 2443-9 PMID: 22644070
  • Schneider BP, Wang M, Radovich M, Sledge GW, Badve S, Thor A, Flockhart DA, Hancock B, Davidson N, Gralow J, Dickler M, Perez EA, Cobleigh M, Shenkier T, Edgerton S, Miller KD, & ECOG 2100 (2008). Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 26 (28), 4672-8 PMID: 18824714

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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Guidelines for HLRCC kidney cancer risk, surveillance and treatment published

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare kidney cancer susceptibility syndrome caused by autosomal dominant mutations in the FH gene. The three main symptoms of HLRCC are red skin papules called cutaneous piloleiomyomas; multiple early-onset uterine leiomyomas; and susceptibility to type 2 papillary renal cell carcinoma.

Clinical guidelines for HLRCC were the subject of a panel discussion at the 5th BHD and 2nd HLRCC Symposium in Paris last summer. The panel was led by Professor Fred Menko, and included Professor Eamonn Maher, Professor Stéphane Richard, Dr W. Marston Linehan, Dr Laura Schmidt and Graham Lovitt, chairman of the HLRCC Family Alliance. The results of this discussion have now been published in Familial Cancer (Menko et al., 2014).

Menko et al. suggest that patients who have histologically confirmed multiple cutaneous piloleiomyomas, or at least two of the following – symptomatic uterine leiomyomas before age 40, type 2 papillary carcinoma before age 40, or a first-degree relative who meets one of these criteria –  meet clinical diagnostic criteria and should be  referred for genetic testing where possible. Up to 24% of families with clinical features of HLRCC have been reported to not have a detectable FH mutation. In these families, immunohistochemical staining of tumours to demonstrate increased protein succination can confirm a diagnosis of HLRCC.

Expert opinion suggests that 15% of HLRCC patients are at risk of developing kidney cancer, most commonly type 2 papillary renal cell carcinoma. The mean age of diagnosis is 41 years, with a range of 11 to 90 years of age. While the risk is low, an estimated 1-2% of patients of HLRCC patients developing kidney cancer before the age of 20, and HLRCC patients as young as 10 have presented with kidney cancer.

Given the aggressive nature of HLRCC-associated kidney cancer, and the fact it can develop at a young age, Menko et al. suggest that DNA testing should be considered from the age of 8-10, although decisions should be made on an individual basis in collaboration with the family. Tumour surveillance should be offered annually from this age to children with a confirmed mutation and to those who are at risk of inheriting HLRCC, but who have not undergone gene testing. MRI is the preferred screening method, using 1-3mm slices through the kidneys in order to find small tumours.

HLRCC renal tumours are usually unilateral and solitary. Tumours tend to be more aggressive, with an increased chance of metastasising, even when the tumour is small, meaning that the 3cm rule and nephron sparing surgery used to manage BHD and VHL tumours is not appropriate. In HLRCC, once a tumour is found, the tumour should be promptly resected with wide surgical margins, and retroperitoneal lymphadenectomy should be considered. Where there is doubt that a partial nephrectomy would be curative, radical nephrectomy should be performed. In the authors’ experience, patients had a good prognosis and showed no evidence of disease when tumours were found early and managed surgically.

Loss of FH leads to dysregulation of the TCA cycle and glycolysis and several therapies targeting these pathways have been recently developed, which may be appropriate systemic treatments for HLRCC patients with metastatic disease. However, access to these treatments is currently only available through clinical trials.

While publication of these guidelines will help clinicians diagnose HLRCC patients and to manage their renal tumours optimally, the authors discuss the need for clinicians to share data internationally in order to ensure that these guidelines meet the needs of HLRCC patients, and can be refined if necessary. In particular, more data about childhood cases of HLRCC renal cancer would help determine the best age to perform germline genetic testing and to start tumour surveillance.

 

  • Menko FH, Maher ER, Schmidt LS, Middelton LA, Aittomäki K, Tomlinson I, Richard S, & Linehan WM (2014). Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment. Familial cancer PMID: 25012257

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

pf button Guidelines for HLRCC kidney cancer risk, surveillance and treatment published

Doctors should consider germline genetic testing in kidney cancer patients under 46

It is estimated that between 5 and 8% of kidney cancers are hereditary (Linehan et al., 2010). There are several clues that help clinicians diagnose these cases: patients who present with multifocal and/or bilateral tumours; who have a family history of the disease; or who are younger than the average age of onset are more likely to have inherited a genetic susceptibility to their cancer.

Correctly diagnosing hereditary cancer cases is important as it may change the chosen treatment pathway, suggest a patient’s prognosis and future risk of recurrence, it allows other family members at risk of developing the disease to be identified, and has implications for family planning.

For some cancers, specific guidelines exist to help doctors identify hereditary cancer cases. For example, in the UK, if a patient, or one of their first degree relatives, presents with breast cancer before the age of 40, the patient should be referred for genetic testing (NICE guidelines, 2013). Currently there are no similar guidelines for hereditary kidney cancers, meaning that referral for genetic testing relies on the patient having a switched on clinician.

A recent study from Dr W. Marston Linehan’s group at the National Cancer Institute (NCI), in the States suggests that germline genetic testing should be considered for all patients who present with kidney cancer before the age of 46 (Shuch et al., 2014).

The authors first analysed the mean age of initial diagnosis in over 100,000 kidney cancer cases from the Surveillance, Epidemiology and End Results (SEER) Program database held at the NCI. The mean age of first kidney cancer diagnosis was found to be 63.4 years old. Subtype analysis of gender, tumour histology, and race showed slight variances in mean age of diagnosis, but these were not significantly different from the overall mean, thus Shuch et al. did not include these factors in their subsequent analyses to define an age threshold for genetic testing.

Next they reviewed the average age of diagnosis of 608 patients with hereditary kidney cancers, recruited through the Clinical Manifestations and Molecular Bases of Heritable Urologic Malignant Disorders trial at the NCI. The dataset comprised 387 VHL patients, 127 BHD patients, 56 HLRCC patients, 25 HPRC patients, and 13 SDH patients, and to be included in the trial, patients needed to have renal cell carcinoma, a clinical diagnosis of one of these syndromes and/or a genetic diagnosis. Overall, the mean age of this cohort’s first kidney cancer diagnosis was 39.2 years, meaning that, on average, patients with hereditary kidney cancers get their first tumour nearly 25 years earlier than patients with sporadic cancers.

In order to define an age threshold before which genetic testing should be performed, Shuch et al. analysed what percentage of hereditary kidney cancer patients would be identified and the number of patients needed to test in order to find a single patient with hereditary kidney cancer. Testing at an earlier age means that while a larger proportion of those tested are hereditary cancer patients, any hereditary cases that develop after that age will be missed. Conversely, testing at a later age means that although more hereditary cases will have had time to manifest, the concomitant increase in sporadic cases means that more patients would have to undergo unnecessary genetic testing in order to identify the hereditary cases.

Thus, the authors found that testing all patients at the age of 46 and under struck an optimal balance between sensitivity whilst ensuring the number of patients tested unnecessarily remained low. With a cut off age of 46, 70% of hereditary cases had manifested by this age, and an estimated 7- 28 individuals are needed to test in order to find a single case of hereditary kidney cancer.

There are a number of confounding factors in this study. The hereditary cancer cohort only included five types of kidney cancer syndrome – and in particular renal cell carcinoma syndromes – meaning that this study is not directly relevant to other kidney cancer syndromes such as TSC. Additionally, it is possible that some cases in the control cohort were undiagnosed cases of familial kidney cancers, which would artificially lower the average age of cancer onset in this cohort. Furthermore, subtype analysis of the hereditary kidney cancer cohort showed that the average age of onset in BHD is later than the others at 50.3, meaning that many BHD cases might not get picked up with routine screening.

Thus, although this study gives clinicians a starting point at which to consider genetic testing in younger kidney cancer patients, a cut of age of 46 should only be considered to be a rough guide.

 

  • Linehan WM, Srinivasan R, & Schmidt LS (2010). The genetic basis of kidney cancer: a metabolic disease. Nature reviews. Urology, 7 (5), 277-85 PMID: 20448661
  • Shuch B, Vourganti S, Ricketts CJ, Middleton L, Peterson J, Merino MJ, Metwalli AR, Srinivasan R, & Linehan WM (2014). Defining early-onset kidney cancer: implications for germline and somatic mutation testing and clinical management. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 32 (5), 431-7 PMID: 24378414

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

pf button Doctors should consider germline genetic testing in kidney cancer patients under 46

Investing in cancer research pays off

In the UK, a significant amount of medical research funding – an estimated £2.9 billion in 2012/13 – comes from the public purse through taxes and charitable donations, or from the Wellcome Trust, so it is important to see whether the resultant health benefits justify this spending. However, conclusively proving that funding medical research benefits society financially is incredibly difficult.

In 2008, the Health Economics Research Group, Office of Health Economics and RAND Europe published the results of a study investigating the financial benefits of investing in cardiovascular disease research, and in mental health research in the UK. This study found that the rate of return was 9% for cardiovascular disease and 7% for mental health, meaning that for each £1 spent on cardiovascular or mental health research, benefits to health costs – for example cheaper treatment, or more effective disease prevention so services were ultimately used less – were 9p and 7p every year in perpetuity respectively. These were both at least double the UK government’s minimum recommended threshold of 3.5%, indicating that the government should view investment in these areas positively.

Building on the methodologies developed for the 2008 study, Glover et al. (2014) investigated the economic value of investing in cancer research. This study was funded by the Wellcome Trust, Cancer Research UK, the National Institute for Health Research, and the Academy of Medical Sciences.

Using data from the National Cancer Research Institute (NCRI) Cancer Research Database, they found that 10 funders, including the Medical Research Council and the Wellcome Trust, accounted for over 95% of the research conducted at the NCRI between 2002 and 2011. Funding data covering the 30 year period between 1970 and 2009 were compiled for these 10 funders, and showed that in this time together they had spent roughly £15 billion (adjusted to 2011/2012 prices) on all cancer-related  research activity.

Next the authors determined which cancer interventions had yielded the greatest difference to health outcomes in the last 20 years. They found the seven major interventions were smoking cessation/ prevention programmes; breast, cervical and bowel cancer screening programmes; and improved breast, prostate and colorectal cancer treatments. In particular, anti-smoking schemes provided 65% of the net monetary benefit seen in this time, making it the most effective cancer intervention analysed.

In order to determine what contribution UK research had to these interventions, the authors analysed the citations used in 31 clinical guidelines commonly used in the UK, and assessed which citations resulted from UK funding. The proportion of financial health gains due to UK-funded research was found to average 17%. However, this analysis does not take into government schemes, such as awareness campaigns or anti-smoking messages on cigarette packages.

The net monetary benefit (NMB) of the seven interventions was sensitive to the quality-adjusted life year (QALY) value.  When the QALY was set at £25,000, all seven interventions were found to show a NMB. However, when the QALY were reduced to £20,000, prostate and colorectal cancer treatments, and breast cancer screening did not yield financial gains on investment. This indicates that the financial gains of these interventions are more marginal, and also illustrates the sensitivity of the analysis.

The overall rate of return for UK government and charitable investment in cancer research was estimated to be 10.1%. However, the average time elapsed between investment and patient benefit was 15 years, meaning that investment in cancer research is a long term one.

This study focusses on common cancers and lifestyle factors, such as breast cancer and smoking. However, research on rare diseases can yield benefits for both rare and common diseases. Rare diseases are often more extreme forms of common disorders, and usually have a more straightforward aetiology, making them easier to investigate than their common counterparts. Research on the rare disease hypercholesterolemia led to the development of statins, which are now commonly prescribed in the UK for high cholesterol, and provide sales revenues worth billions of dollars; and the rare disease alkaptonuria is a good model for  osteoarthritis (Taylor et al., 2011), which affects 1 in 3 people over the age of 45. Additionally, rare diseases are often chronic and disabling, meaning that medical and social care can be costly, both to the patient and to the NHS.

Investment in cardiovascular, mental health and cancer research have all proven to have a positive rate of return on investment. Additionally, increased public investment in research often yields sufficient intellectual property or innovation to attract private investment, further increasing the health benefits gained from public investment (Haskel et al., 2014, a report for the Campaign for Science and Engineering).

Thus, increased spending on rare disease research may prove to be a wise investment for the UK government and charity sector, as developing treatments for rare diseases will not only benefit rare diseases patients themselves, but also has the potential to benefit the wider population with more common forms of those diseases.

 

  • Glover M, Buxton M, Guthrie S, Hanney S, Pollitt A, & Grant J (2014). Estimating the returns to UK publicly funded cancer-related research in terms of the net value of improved health outcomes. BMC medicine, 12 PMID: 24930803
  • Taylor AM, Boyde A, Wilson PJ, Jarvis JC, Davidson JS, Hunt JA, Ranganath LR, & Gallagher JA (2011). The role of calcified cartilage and subchondral bone in the initiation and progression of ochronotic arthropathy in alkaptonuria. Arthritis and rheumatism, 63 (12), 3887-96 PMID: 22127706

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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