Does having CLL really make you 3 times more likely to get (another) cancer, and does CLL treatment add to the risk? - Part 1

[bennevisplace]

1. The risk of developing a Secondary Primary Malignancy

"The higher risk of SPM associated with CLL has been recognized for many years, well prior to the modern therapy era. Manosow and Weinerman in 1975 demonstrated a three-fold increase of SPM and an eight-fold increase of SC in CLL"

Thus reads part of the introduction to a 2021 study of SPMs (secondary primary malignancies, i.e. secondary cancers, whether solid tumours or blood cancers) including SC (skin cancers) in a cohort of 517 CLL patients onlinelibrary.wiley.com/doi...

Since 1975, many studies have shown Manosow and Weinerman's estimates to be exaggerated, or one could say "no longer applicable". For Part 1 of this post I've chosen a fairly recent, large-scale study from the Netherlands to explore how the risk of developing another cancer is affected by a CLL diagnosis. The study nature.com/articles/s41408-... compares the incidence of second primary malignancies (SPMs) among 24,815 CLL patients diagnosed during 1989-2019 in the Netherlands with the expected number of malignancies in the age-, sex-, and period-matched population. The relative risk, as expressed by the standard incidence ratio (SIR) observed, was 1.67 in solid cancers (95% CI, 1.65–1.75) and 1.42 (95% CI, 1.24–1.62) in blood cancers. That means, across all solid tumours, a CLL patient has on average a 67 % higher chance of developing a (second) primary cancer than their counterpart in the general population, and a 42 % higher chance of developing another type of blood cancer. So, nowhere near the threefold risk proposed in 1975.

Although this finding is in line with earlier large scale studies in the USA, Denmark and Australia, the overall relative risk of getting cancer is not an especially useful number to know. We need to understand our absolute risk levels too, and for different types of second cancer, especially the ones that tend to afflict our gender and age group and are life-threatening.

This recent study presents its findings in the form of "forest plots" with data rows alongside, giving the reader an instant visual impression, plus statistical measures of the relative risk (SIR) and the increase in absolute risk (AER) for each type of cancer. Reading these plots is easier than it sounds! Browse the Figures in the article, showing forest plots of different SPMs for CLL patients in the study, according to sex (Fig 1), age (Fig 2), latency time i.e. between diagnoses of CLL and SPM (Fig3), and receipt of antineoplastic therapy i.e. chemotherapy (Fig 4). Also, read the commentary above each Figure.

A number of interesting conclusions emerge:

• Overall, CLL males have a higher relative risk than CLL females of a SPM: SIR 1.70 v 1.55, but because they are more prone to cancer in the general population, CLL males have almost twice the absolute excess risk of a SPM compared with CLL females.

• The absolute risk of a SPM tends to increase with age, while the relative risk of a SPM tends to level off after the age of 60.

• Numerically, by far the most significant SPMs are skin cancers, particularly non melanoma types; the SIR for all skin cancers would exceed 3 (Fig 4).

• Other SPM risks of note are colon, lung and kidney cancer, and soft tissue carcinoma, all with SIRs in the range 1 to 3.

• For several of the SPMs listed the absolute excess risk (AER) is modest to negligible, e.g. myeloid blood cancer, breast, ovarian and endometrial cancers.

• Excess cases of acute myeloid leukemia (AML) seem to be wholly driven by myelodysplasia (MDS) following chemotherapy (Fig 4), although before 2003 and in patients over the age of 70 this chain of events is absent (Fig 2).

• Chemotherapy also increases the risk of skin cancers (Fig 4).

So I'm at risk - what can I do about it except worry?

CLL is an exception, but with other types of cancer the key to survival is early diagnosis. And you can still make choices that should lessen your risk of developing a particular type of SPM.

Skin cancers - the most significant class of SPM for CLLers - are very amenable to early diagnosis and treatment, malignant melanoma being the most feared. Frequent self examination, preferably with the help of a partner to scrutinise your back, in between regular dermatology consultations, is essential.

...and of course, you can reduce your chance of developing skin cancers by covering up while you are outdoors on a sunny day.

Colon cancers tend to be slow growing but symptoms can be vague. CRC screening programmes based on FIT cancerresearchuk.org/about-... are worth doing, though in some countries (UK) the haemoglobin cutoff level is so high that it means that half of carcinomas and three quarters of precancerous adenomas are missed. So it's a good idea to get yourself on a 4 or 5-year schedule of colonoscopies or, failing that, virtual colonoscopies (low dose CT scan), which even the NHS offers, sometimes.

...not forgetting that maintaining a healthy diet can reduce your risk of developing colon cancer.

Lung cancer - apart from smoking, which accounts for 80 % of lung cancer deaths, there may be other primary risk factors that you can change in your favour, see cancer.org/cancer/types/lun...

For other cancers there may be no excess risk of a SPM due to CLL, but don't neglect any community health screening progammes and regular health checks that are on offer.

If these things make you gulp just thinking about them, just remember this:

Fear is a vital emotion designed to spur us into action

Worry/ stress/ anxiety is a state brought on by inaction

Go well.

Edit

A couple of the replies to this post have prompted an addendum.

This post is concerned with the relative risk, or the absolute excess risk of getting a second cancer for those with CLL. It says nothing about your baseline risk, i.e. the absolute level of risk that exists for each type of cancer in the general population. Some of the SPMs mentioned in the study article, e.g. breast, lung and colorectal cancer, are much more prevalent generally than the likes of pancreatic and kidney cancer, see wcrf.org/cancer-trends/worl...

That said, your individual risk may be very different from the average in the population. Genetic risk factors like ethnicity and inherited predisposition are clearly beyond your control; while certain environmental and lifestyle factors may be things you can influence, to swing the odds in your favour.

[AussieNeil Partner Administrator]

Thank you for this excellent summary concerning our risk of Secondary Primary Malignancies. As you note, "the overall relative risk of getting cancer is not an especially useful number to know. We need to understand our absolute risk levels too." Media headlines use the relative risk for dramatic effect. Ten times the relative risk sounds scary, but it is of little concern if the absolute risk is 1 in a million!

Great advice:-

"don't neglect any community health screening programmes and regular health checks that are on offer."

Neil

[Sushibruno in reply to AussieNeil]

🙂

[Sushibruno]

thank you for the last 2 sentences. I fear so much I need this….

[wellbeingwarrior]

Screening, and early advice seeking for concerns, is key to staying above the higher risks. I worry sometimes I appear neurotic (when I never used to be) when I want things checked out early for reassurance.

For me, breast screening picked up breast cancer last year. Cervical screening this year sent me to have a biopsy (results still pending) and annual skin screening has removed two lesions for lab investigation so far. One was pre-cancerous, the recent one came back an inflamed cyst. My dermatologist is well educated on CLL and the risks and has a crack up sense of humour as well. Bonus.

I do worry I am just a sitting duck in relation to SPMs, but can also only do what is in my control (get advice about concerns that arise and stay current with screening).

I do wonder if the breast, ovarian and endometrial cancers low incidence was historically related to the fact more males, closer to 70 were typically diagnosed. All those cancers would typically be diagnosed in younger females (<70). And scientists are smart, but I've always wondered whether they apply stats on those cancers only to females, and not the general CLL population (as a man is unlikely to get any of those).

[mrsjsmith in reply to wellbeingwarrior]

That was my first thought as well when I read it, especially as having tests that are female specific.

Colette

[bennevisplace in reply to wellbeingwarrior]

Thanks for your reply, which reinforces the importance of screening for cancer.

It was one of the replies that prompted me to write an addendum, see edit above.

Regarding possible gender/ age bias, according to the article patients and population were age-, sex-, and period-matched.

[Kiwidi]

I have two scares with skin cancer. Despite having regular checks these have just ‘arrived’ They present as small lesions on the skin that don’t heal- one appeared within weeks of my having a full skin check. Both were SCCs. Not sure what you can do about that but be very vigilant!

[dougstalbans]

A bit of sunshine today so I'll use sunscreen on face as well as covering legs and arms. Doctor's orders. Wouldn't have done 2 years ago. No advice on it from haematologist in 9 years.

[Aerobobcat]

All a bit worrying, but good to have the knowledge and to be aware of the risks, well done!

Aerobobcat

[Mtk1]

I don’t know about elsewhere in UK but I have never seen a dermatologist once in the 7 years since diagnosis. I see in the USA there is regular screening but nothing where I live unfortunately.

Dave.

[Poodle2 in reply to Mtk1]

I had my first dermatology appointment last year, I went privately. My parents live in the Czech Republic so I saw a doctor there. She explained to me that all CLL patients in the Czech Republic are entitled to a yearly dermatology check up which starts 5 years post diagnosis. I will ask my CLL specialist if she could refer me this year. No harm in trying.

[Skyshark in reply to Mtk1]

Same here. But I suspect if you don't ask you don't get. Maybe time to send a photo of every mole etc to CNS.

[mrsjsmith in reply to Skyshark]

Good advice.

I had a reaction to Septrin and I asked to see a Dermatologist. There is one in my hospital that sees all the CLL patients.

Colette

[Poodle2 in reply to Skyshark]

That's exactly my motto Skyshark, if you don't ask, you don't get. I have to say my CLL consultant usually does everything I ask her for, she is very supportive and I feel she cares. She doesn't go just by the book, if she can see something is making me anxious, she tries to help. I appreciate her very much.

[Aerobobcat in reply to Mtk1]

Hi Dave,

There is definitely a lack of continuity regarding dermatology skin examinations for those diagnosed with CLL.

I have been seen regularly by the Royal Marsden cancer hospital since I was first diagnosed with a Basal cell carcinoma on my nose.

Since then I have had 6 procedures for minor skin cancers. I can only assume that it’s a suspected skin cancer that triggers the need for regular skin examinations, but who knows for sure with the way things are these days.

My regards

Aerobobcat

[Mtk1 in reply to Aerobobcat]

It was just my observation that we in the UK have to be our own advocates at times.

Dave.

[Aerobobcat in reply to Mtk1]

Yes, I agree it’s been my view for sometime that we need to advocate for ourselves when things are just dragging on.

[bennevisplace in reply to Mtk1]

I anticipated a UK sub-thread on dermatology exams, because I have first hand experience of how hard it can be to get seen these days.

When I first had a BCC around 2007(?) my GP referred me without hesitation and the derma gave it the liquid N2 treatment with 6 month follow ups. In 2010 my wife noticed a suspect lesion on my back which turned out to be malignant melanoma. Thankfully it could be surgically removed in time. But by then my entitlement to regular derma checks haad expired. I had 5 plus further BCCs and a couple of SCCs removed since, but still no regular derma check until a year ago, and then there's a time limit of 2 years written into the contract.

I know of other folk, under other health trusts in other regions, who get seen regularly on lesser grounds.

Definitely a case of doing your own surveillance, taking no chances if you find anything the least suspect, being your own advocate - i.e. leave no GP unruffled - and press your case as hard as you can.

[Jetliz]

Very interesting and relevant. I had a PET Scan for CLL and found an incidental kidney clear cell renal carcinoma very fortunate that it hadn't spread but its an aggressive cancer and had to have a nephrectomy. I'm still in a high risk category of observation. As well as increased risk of secondary cancers with CLL still. I feel overwhelmed at times but overall you have to be positive, vigilant and live life to the full. Easier said than done at times!

[bennevisplace in reply to Jetliz]

Sorry to hear of your carcinoma, but what good fortune it was picked up early. I do hope that's your entire ration of SPMs accounted for!

[NYCBill]

Bennevisplace—Thank you. The table and your summary were very effective in understanding our risk. Good thoughts. Bill

[ChristyAnne_UK]

All good advice, thank you. I can't read graphs, though.. waiting for cataract surgerym and my vision is very poor. Anything on a white backfround is particularly difficult, so was grateful for the text.

I went through the mill with breast cancer for ten years in the noughties.. tumours on both sides, chemo, radiotherapy, hormone therapy and multiple surgeries, culminating with radical bilateral mastectomies in 2008. Discharged as a cancer patient on 2012. .. two years before CLL diagnosis. (Triggered by chemo, maybe?)

The breast cancer was genetic apparently, as my mother and my aunt had it, too, not far apart, time-wise.

So.. if there's anything else to come, would that make it TPM? Tertiary Primary Malignancy?

Forgive the flippancy, but I consider myself already 23 years into borrowed time! Hallelujah! Avoiding Covid is still the biggest fish for my frying pan, at present. Novid to date, and planning to stay that way as long as possible. All hail the mighty FFP3!

Wishing everyone all the best in dodging all the slings and arrows of our outrageous fortunes, and hope that, by opposing, we will end them.

[bennevisplace in reply to ChristyAnne_UK]

Nice to hear from you Christy Ann. I think you deserve a Novid medal if one exists.

Although your breast cancer preceded your CLL diagnosis, it could still be considered a potential SPM, as you almost certainly had CLL or a precursor lymphocytosis for a number of years before either diagnosis (your bio indicates that you have a slow-progressing form of CLL).

However, as you've pointed out a hereditary link, and as the Dutch study shows little excess risk of breast cancer in CLL patients, we can probably ignore the SPM theory in your case.

Best wishes.

[ChristyAnne_UK in reply to bennevisplace]

I follow the daily digest of posts, and follow you, anyway, so even if I don't say much, I'm keeping up. Yes, my CLL is indolent and not doing much, so others have more of value to offer than I do.

I wondered how long my CLL was around, but it wasn't showing its face. There was a 13 year gap between the first BC dx in 2001 and CLL 2013/14,

[bennevisplace in reply to ChristyAnne_UK]

I just sent you a PM.

[MizLeelee in reply to ChristyAnne_UK]

Hi ChristyAnne, I'm just popping in to say hello as another CLLer who is BRCA2 positive (breast cancer gene). I'm having my ovaries removed preventatively this year (and some of my cousins are having preventative mastectomies, but I've decided not to do that). Good for you for keeping your sense of humor through it all!

[ChristyAnne_UK in reply to MizLeelee]

Thank you, MizLeelee. Just to clarify, my mother and I were tested, and neither of the BRCA genes were found, BUT the geneticist said that with the close cluster of cases in our family, there was likely to be something else genetic going on that hadn't yet been identified. Things may have progressed in the 20-ish years since, of course.

Everyone in my family is aware, but fortunately, this genetic line has come to an end.

[Steffi50]

Whilst I have not found anything on medical websites to explain it, I am always struck by how many women I speak to (and of course CLL is supposedly rarer in women) with CLL who have had or develop breast cancer. I had wondered whether it was the radiation we are given. I 'developed' or found out about my breast cancer five years before I was finally diagnosed with CLL although dodgy blood tests that were misinterpreted suggest I had had it for sometime. So which came first; the chicken or the egg?

[bennevisplace in reply to Steffi50]

It's a good question. My take is that breast cancer diagnosis tends to occur at a younger age than CLL diagnosis, but that doesn't mean they "began" in the same order. Studies of early stage monoclonal B cell lymphocytosis suggest that the key mutations in those cells are present decades before they reach the CLL stage.

[Steffi50 in reply to bennevisplace]

You make a good point. Its those pesky mutations!

[wellbeingwarrior in reply to Steffi50]

Which came first, chicken or the egg? In my case the breast cancer turned up long after the CLL did.

[ChristyAnne_UK]

Awwm bless you, and you make a great point! Thank you. xx

[Kam73]

which came first the chicken or the egg? Excellent question which in don’t think there is an answer. At age 40 I went for my first mammogram and ended up have an excisional biopsy showing a precancerous condition. Years later a more serious sugery for DCIS. Started seeing my breast surgeon for yearly following. In the mean time I faced pre cancers all caught of the thyroid and colon. Also squamous cell carcinoma twice. Melanoma. Then 2 years ago MGUS and CLL. So which came first? Who knows but I often look back and wonder if the TP53 was a factor.

[AussieNeil Partner Administrator in reply to Kam73]

It's possible to have inherited mutations in TP53, such that all body cells are susceptible to developing cancer, putting the individual at high risk of multiple cancers developing - usually earlier in life than typical for any cancers that develop. However, it's more common that during cell division, a stem cell develops a TP53 mutation, increasing the risk of developing a cancer in just that cell line. In other words, most of us with CLL where we have mutated TP53 or del17p, will have functional (unmutated TP53) or a fully intact chromosome 17 in our other body cells. The risk of Secondary Primary cancers in this more common circumstance, comes from the way CLL compromises our immune system. In particular it's how CLL exhausts our cytotoxic T cells, such that they are less effective in their surveillance and removal of precancerous cells.

Neil

[SofiaDeo in reply to AussieNeil]

I had occasion to look at the database of all the listed known types of TP53 mutations, and not all of them were known to be associated with a particular cancer. Some are listed as "unknown effect". There are hundreds of places along the TP53 segment of our DNA, that can mutate. Not all are known to definitely be associated with a cancer. So having a "TP53 mutation" is IMO somewhat similar to saying someone has a "broken leg". Without knowing place, extent, severity, one can't say how awful it actually impacts a person. Is it a slight fracture, in an area easy to heal? Or is someone in a bed with their entire leg in casts, elevated above them and forced to use a bedpan? I think hearing "TP53 mutation" shouldn't automatically make one assume they have the bedpan variant. More of a "well, that may not be so good, I'd rather not have one, have to wait & see."

[Rando21]

Looking forward to part two