8. Mammography benefits: early detection

However, less of a chance to be diagnosed in the last two stages could be more of a benefit with respect to breast cancer (BC) mortality reduction. If we look at the actually screened population, only two stage-4 and eleven stage-3 cancers were diagnosed here, compared to 32 and 27, respectively, in the control group. Reducing the number of deaths by 30% in the control group, to make them comparable with those for 70% attending screening in the treatment group, gives that a woman actually attending screening was 42% less likely to be diagnosed at stage 3, and eleven times (91%) less likely to be diagnosed at stage 4.

But most of the extra cancers in the screening group were diagnosed at stages 0 and 1. Isn't that beneficial too?

Apparently, not. That is what the mortality data in the expanded table suggests: despite as many as 177 more cancers diagnosed at stages 0 and 1, combined, at the end of 10-year period there was

only three deaths attributed to breast cancer fewer
in the screened group (63 vs. 66).

Note that only a small portion of the extra cancers diagnosed at stage 1 or 2 in the screening group have been offset by more cancers diagnosed at later stages in the control group.

That directly suggests two things:

(1) detecting BC early as possible with screening mammography has no appreciable advantage over detecting it early enough, and

(2 most of these extra early cancers in the screened group weren't real cancers at all - rather abnormal growths that showed on a mammogram, but in the control group such growths

never developed into a malignancy.

According to it, in the first ten years of the Malmo trial, those fake cancers accounted for over 20% of all cancers diagnosed in the screening group. Considering that all of the extra cancers diagnosed in this group - 137 of them - were stage 0 or 1, of which the screened group had 176 more diagnoses in all, indicates that 3 out of 4 of those early detected "cancers", were not malignancies at all.

If so, the 83% better chance of being diagnosed at stage 1 or 2 for the screened group effectively

diminishes to some 20%, or so, better chance for the early detected abnormal growth that is actually breast cancer.

That certainly fits much better into the trial's BC mortality figures.

Did the fact that nearly half of BC deaths in the screened group - 31 in 63 - were among the non-attendants, negatively affect mortality rate in the treatment group? If we'd look only at those women who actually attended screening, would it take out one of every two breast cancer deaths, or so?

Let's take a closer look. First, by taking out non-attendants, we are making the screened group smaller. With the reported attendance rate for the trial being slightly over 70%, the actually screened group would have to increase by 40% in order to be size-comparable with the control group. This means that there would be not 32, but 45 deaths.

That would still make screening worthwhile, but there's more to it.

 The much higher death rate (as the number of deaths vs. number of women) among the 6,000 non-attendees in the treatment group - 0.53%, or 71% more than in the control group as a whole - clearly indicates that it constituted a high-risk subpopulation in this respect. The reason for such a high mortality rate is obvious: 77% of cancers in this group were diagnosed at an advanced stage, 3 or 4. It is unlikely that it was due to some higher proportion of fast-growing cancers in this subgroup; with proper randomization, it should be similar to that in the rest of treatment group which attended screening.

More likely,

these are women which for any of possible unknown reasons did not, or could not take as good care of their health as the others, and/or were more vulnerable for no obvious reasons.

Factors such as these cannot be effectively controlled through randomization.

There is no reason not to assume that such high-risk subpopulation existed within the control group as well. In fact, we have to assume this if we are to consider the two groups comparable, which is the basic requirement for trial validity. This high-risk sub-population could have been somewhat larger than in the screening group, or somewhat smaller; we'll assume it was similar in size, since it is plausible, and makes comparison possible.

If so, then the standard-risk sub-group making 71% of the control group would have 0.225% mortality rate. Multiplying it with 21,200 women in this group, gives 48 deaths. Three more than in the screened group which also consists only of the standard-risk participants.

The same figure can be obtained by simply deducting 32 high-risk deaths from the total of 66 in the control group, and multiplying by 1.4 (from 21,200/15,200, the latter being group size after after deducting 6,000 high-risk women) to get the number of deaths for the whole group of 21,200 standard-risk women.

So, assuming that the high-risk sub-population of similar size existed in both, screened and control group, high BC mortality rate among non-attendees within the screening group

does not significantly affect its overall rate vs. that
within control group.

The former still have only about 5% lower BC mortality risk.

But can even this small, statistically insignificant reduction be credited to early detection?

Looking at the data in the expanded table, we can see that among 32 BC deaths in the standard-risk subpopulation of the screened group, 8 (or 25%) were stage-3 and 4 diagnoses. In the control group as a whole, 31 of 65 deaths belonged to that category. Applying the 77% rate for stage 3 and 4 deaths from the non-attendees group to the 31 deaths within the high-risk subpopulation of the control group, gives that 24 of 41 deaths were within this group, and only seven within its standard-risk subpopulation. 

Multiplied by 1.4 to bring them to the whole group size, gives 11 and 10 stage-3 and 4 deaths in the screened and control group, respectively. This implies that the rest of deaths - for stage 0, 1 and 2 diagnoses - total 34 in the screened, and 38 in the control group.

Does that suggest that there is a benefit, even small, from earlier diagnosis due to screening? Not really. Anyone with even basic knowledge in statistics would see at once that

this number of outcomes is too small to provide even reliable indication, let alone evidence of benefit.

Data from all eight trials combined is somewhat more reliable, but the number of trials is still insufficient. Each trial by itself is under-powered in this respect, with a significant chance of random deviations due to it. It doesn't help that only three of them were found adequate.

Best we can say based on the Malmo study numbers is: It is possible that earlier detection helps reduce breast cancer mortality, but we:

(1) don't know how much, and

(2) have no reliable indication it is significant.

What we do know, is that this possible BC mortality reduction benefit is

much smaller than the quite certain increase in rate of pseudo-cancer diagnosed as real cancers due to screening.

In the Malmo trial, there was 31% more breast cancers diagnosed in the screening group for all stages, and 42% more in the early stages (0, 1 and 2). But only a small portion of these extra diagnoses - probably less than a quarter - was actually malignant growth.

It should be noted that the follow up on Malmo trial after this period had the BC mortality reduction for the screening group more than threefold higher, making it unprecedented and unique in all trial follow-ups. At the same time, reliability of the trial data decreased significantly, leaving some doubts with respect to reliability of the reported figures.

Turning back to the advantage of earlier detection by screening mammography, it appears that there is little substance in it. Practically all of the extra diagnosed cancers are stage 0 or 1, and most of them would, according to the longer-term volume of detected cancers in the control (unscreened) group, remain asymptomatic. Unexpectedly,

this diagnostic "advantage" seems to be more likely to be causing harm, through overdiagnosis and overtreatment, than to benefit screened population.

That is probably why those few sufficiently reliable trials did not confirm significant benefit of earlier diagnosis, neither with respect to mortality reduction, nor less invasive treatment.

One piece of the mortality puzzle could be the recurrent cancers, which may be more frequent in the screened population, possibly due in part to their generally higher radiation exposure, with breast compression during screening being additional risk factor. Mortality rate for recurrent cancers is significantly higher, and would at least partly offset the benefit of earlier detection.

Another is that screening mammography is more likely to detect slow-growing cancers, for which an early detection is less critical.

Also, mammography-related overtreatment - initially, repeated mammograms, MRI and/or biopsy for false positives, then possible surgical procedure, radiation and/or hormonal treatment if something suspicious is found and treated without actually being malignant - as well as the related stress shouldn't be neglected as a factor negatively affecting survival rate in the screened population.

Finally, a simple plain number of cancers detected at stage 1, instead of stage 2, does not necessarily directly translate into reduced mortality. What matters is a type of cancer: if, for instance, screened population has higher incidence of more invasive and highly invasive cancers detected between screenings - which could be expected considering mammography radiation risk, false positives and overtreatment - that would also tend to offset statistical benefit of earlier detection.

Putting it all together, there is no doubt that X-ray mammography screening detects more abnormal (not necessarily malignant) growths, generally at an earlier stage than physical breast exam, self-exam, or no screening. But

the benefit from it in terms of breast cancer mortality reduction and, particularly, all-cause mortality reduction, is very elusive.

It is even possible that all-cause mortality is higher for the screened population, offsetting in part, or even exceeding its small BC mortality reduction.

On the other hand, it is all but certain that the increased rate of detection directly contributes to overdiagnosis and overtreatment of the screened population. Thus, the assumed "benefit of earlier detection" due to the higher screening sensitivity may have, in the real world,

turned into a net negative.

It is only due to the prevailing presumptuous attitude about screening benefits and, later, vested interests of those promoting screening and benefiting from it, that it took so long to come to this realization.