Tag Archives: breast cancer

Old paradigms die hard

A statement in a recent Nature editorial [ vol. 554 pp. 308 – 309 ’18 ] had me thinking that a real paradigm shift in our understanding of cancer was under way, but in fact it was an out of date paradigm that tripped up the editorialist.  Since breast cancer is likely to affect us individually or someone we know, it’s worth looking at this paper.

Ductal Carcinoma In Situ (DCIS) of the breast, is breast cancer confined to one of the ducts in the breast bringing milk to the nipple.  If it stayed there forever it would be harmless, like a benign mole on the skin. Unfortunately ‘up to’ 40% of DCIS invades the lining of the duct and the soft tissue of the breast becoming Invasive Ductal Carcinoma (IDC) where it is not harmless at all.  There is currently no way to tell which DCIS will stay quiet so everyone gets treated.

A heroic paper in cell (vol. 172 pp, 205 – 217 ’18 ) used the highest of high technology to study the question.  First they used Laser Capture Microdissection to separate a selected cell from its neighbors by tracing a laser beam around the cell.  Then they used laser catapulting in which energy from an ultraviolet laser propels the microdissected cell into a collection tube.  Then they performed exon sequencing on the collected cells (e.g. they sequenced the parts of the gene coding for protein), comparing cells which were DCIS from IDCs.  Some 1,293 cells from 10 patients were studied.

There was an average of 23 mutations/patient.  “The transition from DCIS to IDC was not associated with a notable increase in the number of mutations.”  “The authors’ main finding is the remarkable genetic similarity of a patient’s tumor cells in these two distinct states”

Hello.

I thought mutations caused cancer and that the more you had the worse the cancer.  Not so in this paper. A paradigm shift indeed.

What’s wrong with this thinking?  Think a bit before reading further.

If you are old enough, you may remember statements that we were 98% chimps based on our genome (or at least what was known of it at the time).  This is because the sequence of the amino acids in our 20,000 or so proteins varies only by 2% from that of the chimp.

That proves it.  Except that it doesn’t.  Amazingly enough, the amount of all 3,200,000,000 positions of our genome coding for protein is under 2%.  So 98% of or genome does NOT code for protein.  It contains the code to determine when, for how long, and where each gene is made into messenger RNA which is then made into protein.

An analogy may help.

This is like saying Monticello and Independence Hall are just the same because they’re both made out of bricks. One could chemically identify Monticello bricks as coming from the Virginia piedmont, and Independence Hall bricks coming from the red clay of New Jersey, but the real difference between the buildings is the plan.

It’s not the proteins, but where and when and how much of them are made. The control for this (plan if you will) lies outside the genes for the proteins themselves, in the rest of the genome (remember only 2% of the genome codes for the amino acids making up our 20,000 or so protein genes). The control elements have as much right to be called genes, as the parts of the genome coding for amino acids. Granted, it’s easier to study genes coding for proteins, because we’ve identified them and know so much about them. It’s like the drunk looking for his keys under the lamppost because that’s where the light is.

On this point it would be very worthwhile to look beyond the genes mutated in both sets of tumors, sequencing their promotors and enhancers.  I think it would likely show profound differences.

No further posts for a while.  We’re going to visit a new grandson, 3 days old, whose parents apparently lack the creativity to name him.

 

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Carly ‘s Cancer

Today Senator Cruz said that Carly Fiorina would be his running mate, should he get the republican nomination. It’s worth reposting (with a few modifications) what I wrote last September about her cancer when it looked like she had a chance of getting the nomination. See the end for why the health problems of our leaders are problems for us all.

Carly Florina had breast cancer surgery (bilateral mastectomy) 2 March 2009 at Stanford University Hospital followed by chemotherapy and radiation. She was given an excellent prognosis for full recovery — https://en.wikipedia.org/wiki/Carly_Fiorina.

So far so good and it’s just over 7 years. But it is reasonable to ask just what her prognosis really is, particularly as she may be our next vice-president. I asked an old friend and colleague who has been involved in research on breast cancer and in many of the clinical trials of therapy over the past 35 years.

So I wrote the following — I’m writing you for some idea what the chances of someone with breast cancer being free for 6+ years (Carly’s surgery was 2/09) will be free for the next 5+? I know that there are all sorts of statistics on survival in breast cancer (because the cohort is so large). If anyone would know them, it would be you.

and got this back

Impossible to answer your question. Too many variables and NO DATA or info. Many people, docs and patients alike call ductal carcinoma in situ,” cancer” but cure rate is 99%. If she was one of those then, of course, she’s likely to be cured . Stage 1 ,luminal A tumors (even though real cancers) have excellent prognoses—probably > 90% cured. For other real cancers Lots depend on stage, hormone receptors ad infinitum. On thin ice lumping anyone into a broad statement without lots more info

just what you’d expect from an circumspect intelligent expert

So I dug a bit more and sent him this

I tried to find out just what type of breast cancer Carly had. No luck, but various newspaper articles show that she did receive postop chemo causing her hair to fall out as well as radiation. Would ductal carcinoma in situ (Dcis) be treated this way? Would stage 1 luminal A tumors be treated this way?

He replied

Dcis definitely no. luminal a probably shouldn’t be. Sounds like a significant cancer. Next issue is did she get antihormonal therapy. Estrogen receptor tumors are the ones that tend to relapse after 5 years. ER neg. tumors while more aggressive overall seldom recur >5 yrs after dx. The radiation part doesn’t mean much unless she had a mastectomy since all lumpectomy patients get radiation. – If she had mastectomy and chemo and radiation it was probably a poorer risk tumor. Even chemo might not be so bad—–we give chemo to node neg tumors which could end up with very good long term prognosis.AMONG RELAPSES in ER pos pts. 15% recur before year 5 and 17% recur after year 5. However overall likelihood of relapse depends on whether or not she had positive or negative nodes and was ER + or Neg. Sorry to be so wordy but prognosis has been improving steadily. I would guestimate that we’re curing about 70% of women with newly diagnosed breast cancer—excluding dcis who are virtually all cured.

I realized that I’d neglected to tell him that she’d had a bilateral mastectomy as well and got the following back after I did.

If she indeed had radiation after a mastectomy as well as chemo it speaks for a more aggressive presentation. Rule of thumb—-post mastectomy xrt reserved for patients with > 4 positive nodes or tumors >5 cm in size. Today, many are giving post mastectomy xrt to 1-3 positive nodes although that was very controversial for years . newer data impies benefit. So, just guessing, but she probably had positive nodes—a poorer prognostic sign for long term—but only if she was estrogen receptor pos. as noted in prior email.

So there you have it — she’s fortunately well presently, but the tumor and prognosis doesn’t sound that good. Still unknown are histologic type of the tumor, presence or absence of spread to lymph nodes (and if so how many), estrogen receptor positivity, which would certainly give us a better idea of her ultimate prognosis (and the country’s should she become president).

I take no pleasure in any of these posts. https://luysii.wordpress.com/2016/04/24/why-hillary-clinton-had-a-stroke-in-2012/ Both Carly and Hillary are brilliant women it would be an honor to know and I wish them both the best. FYI Hillary was valedictorian of her class at Wellesley.

So why write about their potential health problems? Look at the sad saga of Hugo Chavez who claimed he was cured in July elected in the fall with death before he could take office in March of the following year — see https://luysii.wordpress.com/2013/03/05/q-e-d/. Also consider the last months in office of Woodrow Wilson and Franklin Roosevelt and the results of the League of Nations and the Yalta conference when they were both impaired.