Risk of breast cancer in women with schizophrenia: meta-analysed

"In this meta-analysis of 12 cohort studies that included 125 760 women and in which conventional methods of meta-analysis had been used, schizophrenia in women was associated with an increased breast cancer incidence compared with the general population."

That was a primary findings reported by Chuanjun Zhuo & Patrick Triplett [1] following their survey of the peer-reviewed research literature on the topic of breast cancer risk and schizophrenia up to August 2017. The authors caution however that their review of this topic might not be the last word on it - "it is possible that a future study will show a decreased breast cancer risk in women with schizophrenia compared with the general population" - given "substantial between-study variance" among the research literature they examined. Another very good example of how the currency of science is probability and big sweeping generalisations may not necessarily stand the test of time.

"The status of physical health in patients with schizophrenia has become an important topic in health care management research" introduced the the Zhuo/Triplett paper, and with it, important recognition that diagnoses like schizophrenia can lead to an over-emphasis on the psychiatric often to the detriment of the somatic (see here). This, allied to other findings that have suggested that risk of premature mortality from various somatic complaints / diagnoses / issues is potentially heightened in relation to schizophrenia (see here).

Authors located studies fulfilling their study entry criteria, including "schizophrenia identified as exposure at baseline" and "documented incidence of breast cancer on follow-up" and applied their statistical analyses to results. Importantly: "Studies reporting breast cancer–related mortality rather than incidence were also excluded because the mortality outcome may be affected by many factors other than breast cancer incidence, such as comorbidities and treatments." Most of the included studies/data were found to be methodologically sound based on scores on the Newcastle-Ottawa Scale.

Alongside their finding that women with schizophrenia seemed to be at an elevated risk of breast cancer, authors also suggested that "intensive prevention and treatment against breast cancer are warranted for women with schizophrenia." So yes, this means discussing about potentially modifiable risk factors for breast cancer such as alcohol use and obesity (obesity, at the time of writing, being something of a focus for one large cancer charity here in Blighty). But this also means looking at how schizophrenia and its management might also place someone at elevated risk of something like breast cancer as a result of it sometimes being a "hormone-dependent cancer" and, as the authors note, "a significant positive association between plasma prolactin levels and the risk of breast cancer, has been observed." Minus any scaremongering, prolactin elevations have been noted following the use of certain antipsychotic medicines typically indicated for schizophrenia [2] and other conditions (see here). Any additional risk needs to be managed, and managed well.

I don't think anyone should be unduly alarmed by the Zhuo/Triplett results, but rather more mindful of the fact that a psychiatric diagnosis does not disqualify someone from other risks of more somatic conditions / complaints. The key, yet again, is screening and keeping an open mind...

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[1] Zhou C. & Triplett PT. Association of Schizophrenia With the Risk of Breast Cancer Incidence: A Meta-analysis. JAMA Psychiatry. 2018. March 7.

[2] Wu Chou AI. et al. Female schizophrenia patients and risk of breast cancer: A population-based cohort study. Schizophr Res. 2017 Oct;188:165-171.

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Higher cancer mortality rates associated with mental illness

The findings reported by Steve Kisely and colleagues [1] were of some interest recently and their assertion that despite cancer incidence being "the same as the general population for most psychiatric disorders" or even slightly reduced when a diagnosis of schizophrenia was for example received, mortality due to cancer was "increased in psychiatric patients."

Such findings were based on their examination of: "Mental health records [that] were linked with cancer registrations and death records from 2002 to 2007." It follows other work from these authors in this area including that looking at the gap in life expectancy 'from preventable physical illness in psychiatric patients' [2].

Head-scratching (no, not for that reason) aside as to why cancer should be more deadly for those diagnosed with a psychiatric condition, the authors suggest that lifestyle factors such as alcohol or tobacco use probably wouldn't account for the quandary presented. One suggestion however - "inequity in access to specialist procedures" - does invite further investigation on the back of what has been previously reported in the area of psychiatric diagnosis and health inequality (see here for example).

Indeed, 'disparities in cancer-related healthcare provision' was also one of the explanations put forward by one researcher who replied to my tweet about the Kisely paper (and he should know) complete with reference to research backing up this claim [3]. The Mitchell paper found that: "Rates of mammography screening are lower in women with mental illness, particularly women with SMI [severe mental illness]." Whilst this only covers one type of cancer and one type of screening method, the idea that cancer screening and treatment resources may be 'failing' those with a psychiatric diagnosis is an important one also covered by other researchers [4]. Indeed, Martens et al suggested that "good continuity of care by primary care physicians" may mitigate the issues like screening uptake and the idea of a more 'joined-up' service delivery between psychiatry and other branches of clinical care.

Of the various messages to come from the Kisely findings, I'd like to think that a primary one is that of psychiatric diagnoses not appearing in some sort of clinical vacuum with regards to other symptoms and conditions being present and what effect they can have on quality of life. As per my ramblings about autism and the wide spectrum of comorbidities that can and do impact on health and quality of life, we need to be mindful of how presentation of behavioural / psychiatric symptoms can impact on the presentation and treatment of other conditions, many of which are perfectly treatable / manageable in modern medicine.

But the question is not completely answered [5]... and one wonders whether the findings from Minna Torniainen and colleagues [6] on a potential 'protective effect' from antipsychotics on early mortality in cases of schizophrenia might also bring some potential explanation(s) to the table?

To close: The Force Awakens trailer number 2.

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[1] Kisely S. et al. Why do psychiatric patients have higher cancer mortality rates when cancer incidence is the same or lower? Aust N Z J Psychiatry. 2015 Mar 31. pii: 0004867415577979.

[2] Lawrence D. et al. The gap in life expectancy from preventable physical illness in psychiatric patients in Western Australia: retrospective analysis of population based registers. BMJ. 2013 May 21;346:f2539.

[3] Mitchell AJ. et al. Breast cancer screening in women with mental illness: comparative meta-analysis of mammography uptake. Br J Psychiatry. 2014 Dec;205(6):428-35.

[4] Martens PJ. et al. Are cervical cancer screening rates different for women with schizophrenia? A Manitoba population-based study. Schizophr Res. 2009 Aug;113(1):101-6.

[5] Chang CK. et al. A cohort study on mental disorders, stage of cancer at diagnosis and subsequent survival. BMJ Open. 2014 Jan 29;4(1):e004295.

[6] Torniainen M. et al. Antipsychotic Treatment and Mortality in Schizophrenia. Schizophr Bull. 2015; 41: 656-663.

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Kisely S, Forsyth S, & Lawrence D (2015). Why do psychiatric patients have higher cancer mortality rates when cancer incidence is the same or lower? The Australian and New Zealand journal of psychiatry PMID: 25829481

Risk of cancer associated with autism: small but present

Whilst understanding the power that headlines can have, alongside the way that statistics can sometimes mislead and/or be misrepresented, I don't want to shy away from the findings presented by Huey-Ling Chiang and colleagues [1] reporting that: "patients with autistic disorder have an increased risk of cancer."

Curiosity often leads to trouble.

Based yet again on data derived from the fantastic resource that is the Taiwan National Health Insurance database (see here for some other research examples taken from this dataset), authors looked at the medical insurance records of over 8000 young people diagnosed with an autism spectrum disorder (ASD) living in Taiwan. They found something of an excess risk for various groups and various cancers although only actually recording that: "cancer occurred in 20 individuals with autism". I used the word 'only' in that last sentence to demonstrate how rare a cancer diagnosis was to the autism group as a whole; realising however that for those 20 people, receipt of such a diagnosis probably carried all the emotions for them and their families that one might expect following such news.

The Chiang findings reported in particular an increased cancer risk in relation to males over females and that: "The number of cancers of genitourinary system was significantly in excess of the expected number... and increased risk was found in ovarian cancer." What these findings suggest to me is that awareness and screening for cancer should perhaps be more commonplace in various discussions with autism in mind, particularly in light of how receipt of a diagnosis of ASD seems to offer very little protection against various other comorbidity being potentially diagnosed (see here) and where delays in diagnosis of comorbid conditions can potentially lead. Indeed, other research crossing into some cases of autism concluded something similar [2] when it came to cancer screening access.

Insofar as the other literature on this topic, I do want to go through some additional studies. I am shying away from talking too much about the various research which has for example, implicated some genetic issues with an individual autism diagnosis in mind that have also crossed over into cancer research too [3]. Yes, such studies might be important, but genes and cancer is still a very, very complicated area [4] as indeed, is the current collected literature on genes and autism (see here).

Autism and cancer has previously received a rather mixed review when it comes to any sort of correlation/relationship. The paper from Blatt and colleagues [5] reviewing the records of cases of paediatric cancer for signs of autism concluded that there was not a "high concordance" between the two diagnoses. That being said, their slightly lower participant numbers (N=702) than that included in the Chiang study together with the focus on autism being present in those already diagnosed with various cancers could be seen as study/methodological differences.

A few case reports can also be found in the research literature in this area. The case report from Lisa Radcliff [6] provides an interesting account of breast cancer diagnosis and treatment for a woman diagnosed with autism. Detailing a slightly older age group than the Chiang paper included, the Radcliff paper covered various issues - including legal and ethical - associated with the diagnosis and treatment of cancer also taking into account how autism can manifest and to some extent, complicate things. There are other similar report examples about cancer and autism in the peer-reviewed literature [7] I might add.

The findings reported by Kao and colleagues [8] (open-access) suggesting that "there may be an association between autism and specific forms of cancer" is also worthwhile mentioning in this post. Granted, the authors were looking more generally at 'correlating' autism prevalence and "the Incidence of Specific Female and Male Cancers" for possible shared risk factors, so perhaps again slightly different from the Chiang paper. Their findings however that "the cumulative exposure to estrogen from endogenous and external sources is an established risk factor for both breast... and uterine... cancer, the two cancers that appear to be most consistently correlated with autism" is noteworthy and perhaps ties into some other autism research (see here).

Just before I let this topic go, I do want to pass some comment on the [limited] research asserting that a familial history of certain cancers might show more than a passing relationship to at least some cases of autism. I read something about this quite recently and some, it has to be said, rather disparaging comments about the possibility of any overlap. Without trying to make mountains out of molehills, the paper by Erin Ingudomnukul and colleagues [9] represents one of the primary sources of peer-reviewed evidence suggestive of a possible link between certain types of cancer being present in both women with autism and their first degree relatives. To quote: "Compared to controls, significantly more mothers of ASC [autism spectrum condition] children reported (a) severe acne, (b) breast and uterine cancers, tumors, or growths, and (c) family history of ovarian and uterine cancers, tumors, or growths." This perhaps complements some of the more anecdotal data that I've come across down the years but very much implies that a lot more work needs to be done to confirm or refute such findings.

I want to end this post with a reiteration of the relative rarity of cancer occurring when a diagnosis of autism is received despite the headline of an increased risk present in the Chiang paper. I say this not to downplay the fact that autism is seemingly protective of nothing when it comes to other comorbidity, but merely not to sensationalise this area or add any further worry to those with autism or their families.

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[1] Chiang H-L. et al. Risk of Cancer in Children, Adolescents, and Young Adults with Autistic Disorder. J Pediatrics. 2014. 18 November.

[2] Osborn DP. et al. Access to cancer screening in people with learning disabilities in the UK: cohort study in the health improvement network, a primary care research database. PLoS One. 2012;7(8):e43841.

[3] Crespi B. Autism and cancer risk. Autism Res. 2011 Aug;4(4):302-10.

[4] Dawson MA. & Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 2012 Jul 6;150(1):12-27.

[5] Blatt J. et al. Autism in children and adolescents with cancer. Pediatr Blood Cancer. 2010 Jan;54(1):144-7.

[6] Radcliff L. Breast cancer and autism. J Adv Pract Oncol. 2013 Mar;4(2):113-7.

[7] Kim HS. et al. Squamous cell carcinoma of the lung in an autistic child who has never smoked. J Pediatr Hematol Oncol. 2011 Jul;33(5):e216-9.

[8] Kao HT. et al. The correlation between rates of cancer and autism: an exploratory ecological investigation. PLoS One. 2010 Feb 23;5(2):e9372.

[9] Ingudomnukul E. et al. Elevated rates of testosterone-related disorders in women with autism spectrum conditions. Horm Behav. 2007 May;51(5):597-604.

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Chiang, H., Liu, C., Hu, Y., Chen, S., Hu, L., Shen, C., Yeh, C., Chen, T., & Gau, S. (2014). Risk of Cancer in Children, Adolescents, and Young Adults with Autistic Disorder The Journal of Pediatrics DOI: 10.1016/j.jpeds.2014.10.029

New life for beta-blockers

I approach this post with slight trepidation. A touch of anxiety because I do not want it to become some kind of advert for beta-blockers (or any approach for that matter, pharmaceutical or otherwise) for autism or anything else. This despite some interesting news on potential benefits outside of their primary purposes. I will also at this point reiterate my mantra: 'I am not a medical doctor and do not offer anything like medical advice or recommendation'. OK, got your pinch of salt ready?

I am sure that the board rooms of a few pharmaceutical companies were of a slightly more jubilant mood when they heard about this report picked up the BBC recently on the embarkation of a study to examine the potentially positive effect from the use of beta-blockers in stopping breast cancer from spreading (metastasis), based on some earlier research (full-text) findings. I can also imagine that quite a few people whose lives may have been touched by breast cancer also found the news to be important for a slightly different and perhaps more important set of reasons.

The exact process for the effect of beta-blockers on inhibiting the formation of secondary cancers is still the source of some speculation but attention seems to be focusing on the primary activity of such pharmaceutics acting on stress hormones and in particular how beta-blockers block adrenergic receptors so diminishing the effects of catecholamines. It must be added that this is not the first time that beta-blockers have shown activity against cancers either peripherally or directly.

The good news for beta-blockers did not stop there with another feel-good story in this study by Beversdorf and colleagues* on a potential role for propranolol on word fluency in autism. The main effects were that alongside what one would expect (lower blood pressure, stabilising heart rate) there were also some cognitive 'enhancing' effects to be had for the high-functioning participants with autism similar to other research undertaken by the authors. Improved functional connectivity between brain areas has been suggested as a primary effect from propranolol.

There are some potentially very interesting facets to both these stories on beta-blockers. The biochemistry of effect in both cases is bound to be complicated and indeed might (probably) not even be showing the same effect across the different findings. Beta-blockers are primarily used to address cardiac function and hypertension. Outside of what has already been detailed there is some evidence of other effects; for example including a potential anti-parasitic effect as detailed by this review of treatments for Giardia lamblia. Like many pharmaceutics (and nutraceutics), the effects are likely to be numerous.

Before both these reports of a potential effect of beta-blockers on autism and halting metastatic breast cancer came out, I had intended to cover the very delicate subject of any relationship between autism and cancer on this blog. Those that follow Donna Williams will know about her on-going treatment following her diagnosis with breast cancer. Many people will know Donna through her books, speaking engagements and her website (including her blog) about her experiences of autism. She has been very open about her cancer and continues to plot her treatment course and the associated emotions which accompany it. I wish her well. There was also the publication of this paper (open-access)** in the journal Autism Research by Crespi on autism and cancer risk following on from other reports of possible correlations between autism and specifically with breast cancer. I'm not even going to approach the PTEN findings and any onward suggestions from there.

I don't however want to make too much of any commonalities between autism and cancer with the beta-blocker connection because there might not be any. Beta-blockers are not for everyone with autism; that is for sure. One need only look at my post on the medicine cabinet and autism, and specifically the ARI parent survey of interventions to see that. For autism, if it is possible to identify best-responders to the reported cognitive effects however, there are potential openings which perhaps need further exploration bearing in mind the issues of side-effects and contra-indications. As to effect, if it is tied into the adrenergic receptors or functional connectivity, so be it. If it might be due to a more generalised 'anti-hypertensive' effect being witnessed, questions need to be asked about other classes of medication with similar functions such as the ACE inhibitors (e.g. enalapril) alongside their suggested neuroprotective effects are worthy of some autism research consideration also. The accompanying development of mice models of autism offer an ideal platform for examination.

The last words of this post should be given over to beta-blockers, as an example of the realisation that the quite startling array of pharmaceutics currently on the market seemingly offer wide and diverse effects outside of their original design. Some of these potentially therapeutic effects are only now beginning to be revealed.

* Beversdorf DQ. et al. Effect of propranolol on word fluency in autism. Cognitive & Behavioral Neurology 2011. 24: 11-17
** Crespi B. Autism and cancer risk. Autism Research. August 2011.