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Cancer- breast

Primary Care Corner with Geoffrey Modest MD: Is Mammography Useful?

14 Feb, 17 | by EBM

By Dr. Geoffrey Modest

This blog will bring up 2 recent studies suggesting the lack of efficacy of mammography screening coupled with significant overdiagnosis.

  1. An article a couple of years ago looked at screening mammography in the US, with 10 year follow-up of breast cancer incidence and mortality (see Harding C. JAMA Intern Med 2015; 175: 1483).

Details:

  • This was an ecological study of 16,120,349 women 40 years of older who resided in 547 counties reporting in the Surveillance, Epidemiology, and End Results (SEER) cancer registries during the year 2000.
  • 53,207 had a diagnosis of breast cancer and were followed for 10 years.
  • The researchers looked at the extent of the screening in each county, and the results of both breast cancer incidence and mortality (the latter being defined as women diagnosed with breast cancer in the year 2000 who had died from the disease during the 10 year follow-up period). Overall, in the 547 counties, the overall 10-year incidence based mortality was 47.2 per 100,000 cases diagnosed in 2000.

Results:

  • There was a strong positive correlation between the extent of mammography screening and the breast cancer incidence (P<0.001)
  • But, there was no relationship between screening and breast cancer mortality.
  • Each increase of 10 percentage points in the extent of screening was accompanied by:
    • A 16% increase in breast cancer diagnoses, RR 1.16 (1.13- 1.19)
    • Not even a trend to a change in breast cancer deaths, RR 1.01 (0.96-1.06)
  • Analyzing by tumor size, screening led to a higher incidence of small breast cancers (<= 2 cm), but not with a decreased incidence of larger breast cancers (>2 cm )
  • Each increase of 10 percentage points in screening is associated with:
    • A 25% increase in the incidence of small breast cancers, RR 1.25 (1.18- 1.32)
    • A 7% increase in the incidence of larger breast cancers, RR 1.07 (1.02- 1.12)
  • The following figure shows that as the proportion of women had a mammogram in the past two years, the incidence of breast cancer diagnoses increased significantly yet the 10-year mortality did not budge

Commentary:

  • So, pretty powerful large-scale epidemiologic study, finding that mammography led to a large increase in the diagnosis of small cancers, but there was no decline in the detection of larger cancers. This may be the reason why there was no significant difference in the overall death rate from breast cancer by doing mammography screening.
  • What does this mean? It may mean that there are a subset of very aggressive small cancers which spread and cause clinical disease and mortality, and that screening is didn’t help for these. And that a very large number of small cancers that are picked up by mammography are in fact “overdiagnosed” (defined as: tumors that would not have become clinically evident in the remaining lifetime without screening).
  • One would have expected that if screening did pick up small tumors earlier, that over time the diagnosis of larger and less treatable cancers should decrease. It is quite concerning that the number of larger breast cancers in fact continued to increase over the study. And, of course, the goal of screening is to reduce mortality, which was not found in the study. One additional finding was that increased screening would lead to more breast conserving surgical procedures; however they found no evidence of a decrease in extensive mastectomies.
  • Without getting into a lot of detail, the authors present reasonable arguments that this is not just lead-time bias, or ecological bias (this latter happens when looking at group data and assuming that it applies to the individual who may or may not have had a mammogram). Also, there was no association between mortality rates even comparing those counties with much higher breast cancer incidence, reducing the potential bias of comparing counties with very different incidences of breast cancer. But, they also did not have data on women who had therapy or what the risk factors were for the women who developed breast cancer. Also, this was just a 10-year follow-up, and patients may well live more than 10 years with newer therapies, but I would have expected some evident benefit of screening by 10 years (and at least a trend to benefit…)
  • There have been several important changes in technology over the past several decades, some of which may make older studies less applicable now (these older studies are the ones on which current mammogram recommendations are based). On the one hand, the sensitivity of our screening methods is greater and we are picking up much smaller tumors; and, perhaps these smaller tumors are more likely to regress than the larger ones picked up previous, leading to increased overdiagnosis. On the other hand, treatments have improved a lot, and the risk/benefit equation may have changed some. Given the potential harms of overdiagnosis (including surgery, radiotherapy, and chemotherapy), we should be looking at the new balance. In addition, there are interesting advances in genomic profiling, which are helpful in determining how aggressive a tumor is likely to be as well as how intensive therapy should be

So, a large study like this offers interesting insights, especially when looking at likely overdiagnosis (which one cannot determine in an individual patient). As with all screening tests (e.g. PSA), it would be really useful to figure out how to risk stratify patients, with more aggressive screening in those at higher risk. That is much more likely to show benefit for screening then with screening the general population.

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  1. A more recent article look specifically at breast cancer overdiagnosis by mammography screening in Denmark (see doi:10.7326/M16-0270)). The study looked at women aged 35 to 84, from 1980 to 2010.

Details:

  • Denmark had a perhaps unique opportunity to look at the results of mammography screening both because it has rigorous databases (the Danish Breast Cancer Group, DBCG, and the Danish Cancer Registry, DCR) as well as a 17-year screening program which involved 20% of the population aged 50 to 69. This differential access to mammography screening allowed for real-world comparisons to a large, essentially randomized non-screening populations. Clinical breast exams were not included.
  • The DBCG database included 90,665 women aged 35 to 94 who were diagnosed with invasive breast cancer, and 4267 diagnosed with DCIS
  • For the mammography group in DBCG, they divided tumors into two groups: large (>20 mm) and small (<20 mm), considering the large tumors as “advanced” because they are equivalent to T2 or greater in the TNM classification system
  • The screening routine, somewhat different from what we do in the US, was biennial screening with a 2-view mammography on the first round, with 1-view mammography at subsequent screens except for women with dense breasts who always received a 2-view mammogram.
  • The DCR provided individual data on tumor size in women with invasive breast cancer.

Results:

  • For women aged 35 to 69: in non-screening areas the incidence of advanced cancer increased throughout the observation period.
  • For women 70 to 84: in the non-screening areas the incidence of advanced cancer also increased throughout the observation period, and was most pronounced in the later years.
  • The incidence of non-advanced tumors increased in the screening versus prescreening periods, incidence ratio 1.49 (1.43- 1.54), i.e. a 49% increase
  • Looking just at nonadvanced tumors, there were 711 invasive tumors and 180 cases of DCIS that were overdiagnosed in 2010 (overdiagnosis rate of 48.3% including DCIS and 38.6% excluding DCIS
  • There was no reduction in the incidence of advanced cancers through mammography screening.
  • Their conclusion: “it is likely that one in every three invasive tumors in cases of DCIS diagnosed and women offered screening represents overdiagnosis (incidence increase of 48.3%)”

Commentary:

  • This study is quite remarkable since it is reasonably close to a really large-scale randomized controlled trial, in which for 17 years 20% of women got mammograms and the rest didn’t. And there was no difference in advanced breast cancers through consistent mammography screening
  • See below for other blogs on the poor utility of mammography screening, also showing almost no decrease in breast cancer mortality but large numbers of overdiagnosed mammogram-detected cancer.
  • A lot of the “overdiagnosis” is from DCIS (about 25% of all new breast cancer diagnoses), which the National Cancer Institute now classifies as a “noninvasive condition” (an observational study of 108,196 women with DCIS in the SEER registries found an overall breast cancer death rate of 3.3% over 20 years, similar to the general population: see Narod SA. JAMA Oncol 2015; 1(7):888
  • All of this reinforces the fact that early detection of breast cancer is fraught. For breast cancer, there are 230,815 diagnoses/year in women, 2109 in men; and 40,860 breast cancers deaths/year in women and 464 in men, and affects 1 in 8 women!!!; yet mammography screening has perhaps minimal benefit. Which really brings up the issue of prevention (which, it turns out, does not get much funding). As noted in prior blogs, one big unknown is the prevalence of industrial toxins (many of which are estrogenic, including pesticides, BPA, others used in plastics, etc etc) which are in our environment and may well be carcinogenic. Large numbers of new chemicals are being used and thousands of new ones are introduced each year with minimal attempts to look at potential toxicity. In addition, it is reasonably clear from the studies that healthy diet, weight control, and exercise are helpful. It seems to me that it would likely be much more useful to devote our national resources into preventing breast cancer by regulating environmental toxins and promoting healthy lifestyles than attempting early detection.

See http://blogs.bmj.com/ebm/2016/10/13/primary-care-corner-with-geoffrey-modest-md-radiologist-variability-in-mammography-readings/ which documents the quite remarkable discordance in radiologists’ reading of breast densities

See http://blogs.bmj.com/ebm/2014/02/13/primary-care-corner-with-geoffrey-modest-md-mammography-another-hit/​ for the 25-year results from the Canadian National Breast Screening Study finding NO benefit from mammography screening but that 22% of mammography-detected breast cancers were overdiagnosed.

See http://blogs.bmj.com/ebm/2014/04/22/primary-care-corner-with-geoffrey-modest-md-mammograms-again/ for a 2014 meta-analysis, finding that mammography yielded very small changes in breast cancer mortality (e.g. screening women in their 50s would lead to 3-32/10,000 decrease in breast cancer mortality, but have 6130 false positive and 30-137 overdiagnoses)​. As mentioned above, these studies were older ones.

Primary Care Corner with Geoffrey Modest MD: Breast Cancer Risk and Mediterranean Diet

16 Nov, 15 | by EBM

By Dr. Geoffrey Modest

The PREDIMED study was a large dietary intervention trial which assessed different diets and looked at the subsequent development of invasive breast cancer (see JAMA Intern Med. 2015;175(11):1752-1760​). This was a single-blind randomized controlled field trial done in Spain from 2003-2009 looking at several different outcomes (see below). Breast cancer was a prespecified secondary outcome in women without a prior history of breast cancer.

Details:

  • 4282 women aged 60-80 at high cardiovascular risk  (mean age 67.7, BMI 30.4, 3% on hormone replacement therapy) were randomized to a Mediterranean diet supplemented with EVOO (extra-virgin olive oil), Mediterranean diet supplemented with mixed nuts, or a control diet with advice to decrease fat intake (the Mediterranean diet groups got free supplementary foods; after the first 3 years the researchers became more aggressive in outreach to the control group in an attempt to make the contacts from researchers more equal) and were followed a median of 4.8 years.
  • Achieved diet composition was pretty similar for total calories (approx 2000/d), % protein, % carbs, % fiber, % polyunsaturated fats, though there were strong trends for increased monounsaturated fats in both Mediterranean diets, a-linolenic acid in the nut diet, % EVOO in the EVOO diet (22%, vs 12.5% in the nut diet and 8.8% in low fat, but there was concomitant different % refined olive oil in the EVOO diet of 0.8% vs 5.9% in the nut diet and 6.7% in low fat: i.e., the total % of energy from olive oils was actually not so different between the groups). There was a pretty similar consumption of saturated fats (9.8% of energy in each of the Mediterranean diets and 8.8% in the low fat one).

Results:

  • 35 confirmed cases of invasive breast cancer
    • 1/1000 person-years in those on Mediterranean diet with EVOO
    • 8/1000 person-years in those on Mediterranean diet with mixed nuts
    • 9/1000 person-years in those on the low fat diet
  • Multivariable-adjusted hazard ratios:
    • Mediterranean diet with EVOO vs control: HR 0.32 (0.13-0.79)
    • Mediterranean diet with nuts vs control: HR 0.59 (0.26-1.35)  [ie, not significant]
    • Analyzing by annual cumulative updated dietary exposure: each additional 5% of calories from EVOO: HR 0.72 (0.57-0.90)

I have sent out a few previous blogs on the PREDIMED diet: one showing that the Mediterranean diet supplemented with EVOO was associated with lower likelihood of developing atrial fibrillation (see http://blogs.bmj.com/ebm/2014/06/24/primary-care-corner-with-geoffrey-modest-md-olive-oil-and-atrial-fibrillation/ ), one showing that this diet was associated with primary prevention of coronary artery disease (see http://blogs.bmj.com/ebm/2014/01/21/primary-care-corner-with-geoffrey-modest-md-mediterranean-diet-and-cad-primary-prevention/​ ), and one finding lower likelihood of developing diabetes (see http://blogs.bmj.com/ebm/2014/01/21/primary-care-corner-with-geoffrey-modest-md-mediterranean-diet-for-diabetes-prevention/ ).There was another PREDIMED study finding improved cognition in those on either of the Mediterranean diets (see  J Neurol Neurosurg Psychiatry 2013;84:1318–1325)

So, this present study does raise several issues:

  • There were a small numbers of events, so the results need to be confirmed by larger, longer-term RCTs.
  • The amount of EVOO consumed was pretty significant: there was a statistical benefit only in those consuming >15% of their cumulative energy intake from EVOO and increasing benefit with higher intakes.
  • ​It is unclear from this study design whether the benefit was from the high mono-unsaturates associated with olive oils overall, or to the higher concentration of polyphenols in EVOO (though the actual achieved olive oil consumption, as noted above, supports more the role of EVOO itself, since the actual total % of energy from all olive oils was pretty similar between the groups). There are some other data suggesting that some of the olive oil monounsaturates are associated with antiproliferative effects on human oncogenes and with decreased DNA oxidative damage. But olive oil polyphenols from EVOO have some effect in “inhibition of tumor growth and proliferation, migration, and invasiveness of breast cancer cells in vitro and in vovo breast cancer models” as well as increased apoptosis of cultured breast cancer cells.
  • ​One important point here is that this was a randomized intervention trial. Prior epidemiologic studies have found mixed results on the role of fat in increasing breast cancer risk, but these have been observational studies (the data are more consistent for alcohol as a “dietary” risk factor). The choice of the Mediterranean diet in PREDIMED was because of observational data that heart disease and breast cancer, for examples, are lower in Mediterranean countries than in the US or Northern/Central Europe. A secondary outcome of the old Lyon Diet Heart Study, a 4 year study of 605 patients with coronary heart disease, had found a 56% risk reduction for total deaths and a 61% risk reduction for cancers, though not specifically breast cancer, in those on Mediterranean diet vs low fat diet (see Arch Intern Med 1998; 158:1181).
  • ​But this study does raise, I think, the important point that a healthy diet has an array of benefits throughout the body. We in medicine are often so focused on one part of the body (should we lower the cholesterol to prevent heart disease?) that we may miss the big picture (in this case, the Mediterranean diet seems to be good for the heart, the brain, the pancreas, etc.). And this myopia in part leads to the finding in patients who take statins that they actually eat worse than before the statins (well, after all, the patient is taking a statin, their lipids are pristine, so all is good) — instead of our continuing to reinforce the multitude of known (and unknown but likely) benefits of eating healthfully.​

Primary Care Corner with Geoffrey Modest MD: Mammography screening, again, from another perspective

12 May, 15 | by EBM

By: Dr. Geoffrey Modest

This editorial is from Eric Topol, and raises concerns about the utility of mammography screening . one issue not addressed by him is primary prevention of breast cancer by decreasing environmental exposure to carcinogens: there are thousands of new chemicals developed in the US each year; historically many of them have estrogenic effects (which may not be the only way that breast cancer is stimulated); they seem to make their way into our air, water, and food supply; and essentially none of them have any significant safety checks prior to being mass-produced and released.

So, I agree with Topol that mammography is a terrible test in many ways, and in particular that it prevents so few breast cancer deaths in the current setting where breast cancer is the second leading cause of cancer deaths in women (in 2013 total of 273K women died of cancer, 72K from lung and 39K from breast).  I did post about the new USPSTF recommendations recently, and this and other breast cancer screening blogs can be found here. Topol brings up the intriguing suggestion that maybe we can risk-stratify women, such that low risk women (esp low genetic risk) might not get screening mammograms at all, where the likelihood of a false positive is very high, along with the attendant issues of anxiety, medicalization, followup testing, invasive biopsies, more potentially cancer-causing xrays, and even unnecessary toxic chemo/radiotherapy. and mammograms could be used for more targeted higher risk women. needless to say, this would need to be tested…

 

Primary Care Corner with Geoffrey Modest MD: USPSTF breast cancer screening recommendations

30 Apr, 15 | by EBM

By: Dr. Geoffrey Modest

The US Preventive Services Task Task Force just published a draft recommendation for breast cancer screening in women after age 50 (see here), as follows.

For women 50-74 years old, screening mammography every 2 years, grade B recommendation (moderate certainty that there is net benefit):

–meta-analysis suggests that screening 10,000 women age 50-59 over 10 years will result in 8 fewer breast cancer deaths; screening 10,000 women age 60-69 over 10 years will result in 21 fewer breast cancer deaths. These data are from really old studies. It is likely that current screening may detect more cancers but also that current treatment will decrease the deaths

​–harms of screening: most important is overdiagnosis and overtreatment. Hard to know for sure what the % is, depends on modeling methods used, but it is likely that the increased sensitivity of mammography screening leads to more overdiagnosis. Estimates range from 0% to 54%, but the accepted number is that about 20% (1 in 5 women) are treated for a cancer that would never have been discovered without the mammography and would not have led to health problems.  The other screening harm is false-positives leading to more imaging/biopsy. The data from the Breast Cancer Surveillance Consortium (BCSC, collaborative network of 5 mammography registries plus 2 others with linkage to tumor registries): per 10,000 women screened once: 

–age 50-59 — 932 false positives; 60 biopsies performed for each case of invasive cancer; 11 false-negative mammograms (missed cancers). 

–age 60-69 — 808 false positives; 30 biopsies for each case of invasive cancer; 12 false-negative mammograms. 

–age 70-74 — 696 false positives; 30 biopsies for each case of invasive cancer; 13 false-negative mammograms. 

–frequency of screening: no direct data from clinical trials, but looking at the current trials with screening intervals o f 12 to 33 months, there was no clear trend to benefit in more frequent screening for different starting ages. Observational evidence that there was no difference in breast cancer deaths in women >50 screened biennially vs annually

​–when to consider stopping screening: this data is based on modeling, since there are inconclusive data on 70-74 yo women. USPSTF does not recommend screening 70-74 yo women with moderate to severe comorbid conditions (moderate=cardiovascular disease, paralysis, diabetes; severe=AIDS, COPD, liver disease, renal failure, dementia, CHF, MI, ulcer, rheumatologic disease and combo of moderated conditions).

For women 40-49 years old, grade C recommendation (selectively offer screening, based on professional judgment and patient preferences. moderate certainty that net benefit is small vs more common harms). Still suggesting biennial screening.

–breast cancer deaths avoided by repeated screening of 10,000 women over 10 years = 4.

–harms of mammography for 10,000 women screened once: for age 40-49: 1,212 false positives; 100 biopsies done to find 1 case of invasive cancer; 10 false-negative mammograms. 

–frequency of screening: as with 50-74 year olds (above)

–consider starting at age 40 especially in women with first-degree relative (parent, child, sibling) with breast cancer (increases risk 2-fold)

Comparing starting at age 40 vs age 50:

–life-time benefits for biennial screening mammograms per 1,000 women (note: this is per 1,000 women vs the 10,000 in other data above)

–age 40-74: reduced breast cancer deaths 8; life-years gained: 152.  harms: false positive test 1,529; unnecessary biopsies 204; overdiagnosed breast cancers 20.

–age 50-74: reduced breast cancer deaths 7; life-years gained: 122.  harms: false positive test 953; unnecessary biopsies 146; overdiagnosed breast cancers 18.

–10-year cumulative probability of false positive​ mammogram or biopsy:

–begin at age 40: annual mammograms with 61.3% having false positive, 7.0% with false-positive biopsy recommendation

Biennial mammogram with 41.6% having false positive, 4.8% with false-positive biopsy recommendation

–begin at age 50: annual mammograms with 61.3% having false positive, 9.4% with false-positive biopsy recommendation

​Biennial mammogram with 42.0% having false positive, 6.4% with false-positive biopsy recommendation

For women age >75: insufficient evidence, though some models do suggest continued benefit after age 74 (these are all mathematical models, no real clinical data)

Tomosynthesis (3-D digital mammography): insufficient data for use as primary breast cancer screening strategy, though there may be reduced recall rates for false-positives, and does expose women to twice the radiation

Breast density: BCSC data suggest that 25 million women (43%) have heterogeneously or extremely dense breasts, and % is highest in those age 40-49. increased breast density is associated with higher risk of breast cancer (though not increased risk of dying from breast cancer), and is associated with lower sensitivity (from 87% to 63%) and specificity (from 96% to 90%) of mammography. So, women with increased breast density are at increased risk of false-positive test, unnecessary biopsy, and false-negative test. For women aged 40-49 (but not other groups), there are data suggesting that those with extremely dense breasts have more benefit from annual vs biennial screening.

Other modes of screening, esp in women with dense breasts (eg, breast ultrasound, MRI) — insufficient evidence to recommend.

One of the big unknowns with breast cancer screening is around overdiagnosis and specifically with DCIS (ductal carcinoma in-situ). The incidence of DCIS increased dramatically now that mammography is routine, from 6 to 37 cases/100K women/yr. DCIS is not necessarily a cancer (there is a movement underfoot to reclassify it as not a cancer)​ in that it is in most cases localized/confined to the mammary ductal-lobular system and does not metastasize, there is no good way to differentiate the majority of regular DCIS from the unusual ones that do metastasize, and the current treatment of DCIS is pretty aggressive (lumpectomy/mastectomy, then maybe tamoxifen) — ie, this is a big hole in our knowledge base and needs more research. Another big issue is the ethnic/racial disparity: African-American women have a slightly lower incidence of breast cancer (127 cases/100K, vs 133 cases/100K in white women) yet a significantly higher mortality. ??role of socio-economic status/access to care (which is undoubtedly part of the issue in many areas of the country) vs biology — are there underlying biological differences leading to the finding that Af-Am women tend to have more aggressive and treatment-resistant tumors (eg with triple-negative phenotypes, and more dysplastic tumors), which, by the way, tend to be less amenable to screening?

So, I think these recommendations overall are pretty appropriate. The efficacy of screening is higher in the older age group (median age of cancer diagnosis is 61, and the above numbers confirm increased utility in the 60-69 yo age group). Based on modeling data a few years ago, I have been advocating biennial exams in order to decrease the risk of radiation exposure, and most of my patients are very open to that. I do offer screening at age 40, though I try to make it clear that this is an individual choice, that though there may be some benefit, there are also clear risks of overdiagnosis/increased likelihood of needing more xrays (additional radiation) and biopsies.

For past blogs, see:

Here for a review of the inconsistencies in breast biopsy interpretation

This one goes through more about the risks of screening, utility of using meds in high risk women as cancer prevention, and the need to look into environmental toxins to prevent breast cancer from happening in the first place

This one also critiquing the low efficacy of screening (it should be done, but overall it is not having a huge impact on breast cancer survival)​.

Primary Care Corner with Geoffrey Modest MD: Discordance in interpreting breast biopsies

23 Mar, 15 | by EBM

By: Dr. Geoffrey Modest

One factor often not considered in the breast cancer screening algorithm is the accuracy of the pathology report after biopsies. The widespread use of mammograms has led to lots of biopsies (1.6 million women in the US each year), with a reported approx 25% being positive for cancer. From 2011 to 2014 highly experienced pathologists from 8 states reviewed slides and the concordance of their readings was assessed (see JAMA. 2015;313(11):1122-1132​).

jama

 

Results:

–65% of the invited pathologists consented to participate (n=115) and each given 60 slides to review from a total of 240 cases (1 slide/case), including 23 cases of invasive cancer, 73 of ductal ca in situ, 72 with atypical hyperplasia (atypia), and 72 benign cases without atypia

–49% of cases were in women 40-49yo, 50.8% had either heterogeneously dense or extremely dense breast tissue on mammogram, 57.5% were from core biopsies/42.5% excisional

–Pathologist impressions of the slides (all rated 1-5): confident of assessment (1 being very confident) 81% were 2-3; challenge of interpreting (1 being very easy) 78% were 3-4

–The overall concordance rate of diagnostic interpretations between the pathologists was 75.3% (CI 73.4%-77.0%), or 5194 of 6900 interpretations

–Higher discordance was found in women with higher breast density on mammograms (73%) vs lower (77%) (p<0.001) and in pathologists who interpreted lower weekly case volumes (p<0.001), or worked in smaller practices (p=0.034), or nonacademic settings (p=0.007)

–There was also variation depending on the diagnosis:

–benign without atypia (number of interpretations = 2070): concordance rate was 87%, overinterpretation rate 13% (most of the incorrect ones were read as atypia, some DCIS, but several read as invasive carcinoma)

–atypia (number of interpretations = 2070): concordance rate was 48%, overinterpretation rate 17%, underinterpretation rate 35% (most of the incorrect ones were read as DCIS or benign, a few as invasive carcinoma)

–DCIS (number of interpretations = 2097): concordance rate was 84%, overinterpretation rate 3%, underinterpretation rate 13% (most of the incorrect ones were read as benign or atypia, but quite a few as invasive carcinoma)

–invasive ca (number of interpretations = 663): concordance rate was 96%, underinterpretation rate 4% (most of the incorrect ones read as​ DCIS, but there were a few read as benign)

So, there are obvious issues here. It is quite disturbing the degree of variability here, with even totally benign tissue occasionally read as invasive carcinoma and vice versa. Though there are a few caveats. Only one slide per case was available, and in real practice if a question arose, the pathologist would likely check other cuttings/slides. Also, in real life the pathologist might have asked a compatriot to give their opinion. But this study shows that there is significant potential here for errors, creating unnecessary extreme anxiety, incorrect and potentially devastating therapy (chemo,radiation and surgery), or, on the other hand, missing a potentially curable lesion. I think the lessons here are:

–It is reasonable and appropriate for us in primary care to question the pathologist interpretations (ie, they are not always accurate, and i think at least many of us do incorrectly consider them to be a gold standard)

–And perhaps there should be structural changes to how slides are read:

–it seems reasonable to ask pathologists to somehow rate the certainty of their interpretation when they submit a diagnosis (ie, my guess is that the accuracy was higher when the pathologist looked at a slide and felt certain of their interpretation, which happened rarely in the above study)

–perhaps pathologists should regularly look at more than one slide per biopsy, to potentially give them a better ability to self-monitor and self-correct their first interpretation

–perhaps there should be a routine system of getting second opinions on the slide reading​

Primary Care Corner with Geoffrey Modest MD: Double mastectomy not improve survival

11 Dec, 14 | by EBM

By: Dr. Geoffrey Modest

There was an important note of caution in an article in JAMA, finding that more women are getting bilateral mastectomies to treat unilateral cancer, with data suggesting this might be harmful (see doi:10.1001/jama.2014.10707). This was observational cohort study in the population-based California Cancer Registry from 1998-2011, with median follow-up of 89.1 months. Findings:

–189,734 patients with unilateral early-stage breast cancer were followed. Excluded those with tumor >5cm/paget’s/mammographic diagnosis only.

–Rate of bilat mastectomies was 2.0% in 1998, increasing to 12.3%!!! in 2011. unilateral decreased from 46.3 to 33.4% and breast-conserving surgery with radiation was pretty stable at 51.7 to 54.2%.

–More specifically, re: bilateral mastectomies:

–In those <40yo, the rate increased from 3.6% to 33%

–Was more in those receiving care in National Cancer Institute-designated cancer center: 8.6% vs 6.0%

​–Was most common in non-Hispanic whites at 6.9%, others in the 3-5% range; unilateral mastectomy more common in racial/ethnic minorities — Filipina 52.8%, Hispanic 45.6%, vs non-Hispanic whites 35.2%

​–Tracked with neighborhood socioeconomic status quintile​ (highest rate in highest SES communities). also with private insurance (7.7%) vs public/medicaid (3.3%). unilateral mastectomy also more with public/Medicaid insurance 48.4% than with private insurance (36.6%).

–10-year mortality, compared with breast-conserving surgery with radiation (16.8%): unilateral mastectomy 20.1%. Bilateral mastectomy 18.8% (nonsignif difference for bilat)

So, large increase in bilateral mastectomy in certain populations (esp privately-insured non-Hispanic whites who went to NCI-designated cancer centers), with no evident benefit after 10 years (of note, their Figure 2 shows data up to 15 years post-surgery, with leveling off of curves from 12-15 years). Those with unilateral mastectomy did worse in this and other observational studies. what are the factors explaining these changes? Those with unilateral mastectomy may have had tumors with worse prognosis (eg lymphovascular invasion or extranodal extension — items not recorded in this registry). And the above data suggests a shift from unilateral to bilateral mastectomies. Perhaps part of the issue is the role of breast MRI, which finds all kinds of difficult-to-interpret abnormalities, perhaps leading to more aggressive/bilateral surgery (ie, too much information….). Role of genetic testing (though there are pretty good short-term outcome data that bilat mastectomy is associated with improved prognosis in those with BRCA 1/2, though that is a small % of breast cancers).  But, not surprisingly, bilateral mastectomy is associated with more adverse effects (including both those directly related to the surgery, such as flap failure, necrosis, infection, as well as some studies reporting bad effects on body image, sexual function and quality of life). Bottom line: we will probably never get a clear RCT with definitive answers, so we do need to look at these observational studies. Lots of data are collected in the cancer registries, but we can never be sure that there wasn’t a significant bias in who got more extensive surgery. But women should understand that for other than those positive for BRCA 1/2, the current observational data do not support a clinical benefit from more aggressive surgery and that there are real potential hazards. By the way, there is a really great book “The Emperor of All Maladies” by Siddhartha Mukherjee, which tracks the history of cancer and how its conception and approach to therapy over time reflects the overall dominant social ideology of the period; the book has a special focus on breast cancer.

Primary Care Corner with Geoffrey Modest MD: Mammograms, again

22 Apr, 14 | by EBM

the boston globe ran a story earlier this month pointing out the marginal benefit of mammography from a recent analysis –see below, but they had a thoughtful summary (see here)

the article came out in JAMA (see doi:10.1001/jama.2014.1398) and reinforces the not-so-great efficacy of mammog screening, confirming what i posted in several blogs. they did literature search finding 8 large RCTs (all done between the 1960s and 1990s, which may be an issue: see below) finding a 15-20% decreased breast cancer mortality. another meta-anal from canadian task force found 19% decrease after 11.4 yrs of followup. the new JAMA data (see tables below) includes the relative risk (RR), absolute risk reduction (ARR), overdiagnosis (detected tumors on screening that would never become clinically evident. mostly DCIS, but some suggestion that may also be some invasive cancer diagnoses). this article is available for free, so i am reproducing their results below.

table 1: pooled results from RCTs on mortality reductions with mammog screening by age group

Age Total events in group/total number       Mammog grp           Control grp RR with
mammog
 ARR with mammog Number needed to screen
39-49 448/152300 625/195919 0.85 (0.75-0.96) 0.0005 1904
50-59 361/78465 410/69849 0.86 (0.75-0.99) 0.0007 1339
60-69 110/19093 155/18377 0.68 (0.54-0.87) 0.0027 377
70-74 42/5073 36/4859 1.12 (0.73-1.72 NA NA

 

table 2: estimated benefits and harms of mammog screening in 10,000 women with annual mammog over 10 year period

Age # Diagnosed with invasive unnecessary breast ca or DCIS over 10 yrs # Breast ca deaths in next 15 yrs # Deaths averted with screen over next 15 yrs Overdiagnosis during 10 yrs # With >=1 false pos during 10 yrs # With >=1 biopsy during 10 yrs
40 190 27-32 1-16 ?-104 6130 700
50 302 56-64 3-32 30-137 6130 940
60 438 87-97 5-49 64-194 4970 980

(note: the “# of breast ca deaths in next 15 yrs” column is the number who would die even if they were screened)

they point out that these studies were of women of average risk and the benefit would likely be greater if women at higher risk. for example 4 microsimulation (ie mathematical) models found that women 40-49 with Gail model score twice average and given biennial screen would have same ratio of benefit/harm as woman>50 with average risk.

so, this is a very complex issue. this article confirms the pretty paltry benefits of mammography screening (although average lifetime risk of breast cancer is 12.3%, aggressive mammog screening will avoid breast cancer mortality in only 3-32 of 10,000 women screened in their 50’s, with 6130 having false positives, 940 getting biopsies, 30-137 with overdiagnosed breast cancers) and does not include the fact that treatment is much better now than when the studies were done, and does not even mention that all these mammograms are likely (by mathematical modeling) to create some cancers. also important to note that the differences in breast cancer mortality do not translate into differences in all-cause mortality (prob in part because the numbers saved by mammog is really so small). attempts at provider/patient shared-decision-making so far have probably not been adequate (eg, no change in mammog ordering after USPSTF came out with guidelines to decrease mammogs to every other year and only in women 50-74.  also, boston globe comments on 2010 study of 460 women, where >96% reported that MD discussed benefits of screening but <20% discussed risks).  be aware that the suggestion of doing individualized risks, esp those 40-50 yo, (Gail model etc) makes sense mathematically, but there are no real-world data. also that the array of imputed breast cancer risk factors (inc BMI, dec bone density, smoking, alcohol, estrogen/androgen exposure, late age of first pregnancy…) are absent in 60% of women with breast cancer.  which also (again) raises the elephant-in-the-room: the huge numbers of industrial toxins in our environment, food chain, water… which may well be a really major cause of breast cancer (the vast vast majority never adequately tested, but we do know of many so far which have hormonal stimulatory  effects on breast tissue). but in the context of mammog, i think it makes sense to discourage women under 50 from getting mammog, and doing mammog every 2 year in women aged 50-74 (there are pretty good data that every other year testing is just about as sensitive and fewer false positives… and also less radiation)

geoff

Primary Care Corner with Geoffrey Modest MD: Mammography, another hit

13 Feb, 14 | by EBM

25-year results fro the Canadian National Breast Screening Study just published in BMJ open access (see doi: 10.1136/bmj.g366), finding no benefit from mammog screening and that 22% of mammog-detected breast cancers were overdiagnosed!! lots of data from the study, will include since allows a more critical understanding.

study methodology:

–15 screening sites in Canada assigned 90K women aged 40-59 randomly to mammog (5 annual mammos) or control, ending in 1988
–all women had clinical breast exam (CBE) and were taught self-exam
–women 40-49 received an initial mammo, then randomized (irrespective of clinical exam) to annual (ie, another 4) plus CBE vs no mammog/just usual care
–women aged 50-59 randomized to 5 mammos and CBE or just CBE (in this group, felt unethical to have a “no screen” arm)
— high adherence to groups: 90% completed mammos in the mammo group

follow-up (up to 25 years after randomization):

–1190 breast cancers diagnosed (666 in mammog arm, 524 in control)
–5193 cancers found during followup period (2584 in mammog arm and 2609 in control)
–of the 666 cancers dx’d in the mammog arm during the study, 484 were screen-detected, 176 were interval cancers
–size of cancer in mammog arm was 1.9 cm vs 2.1 cm in control arm
–in mammog arm: 30.6% of cancers detected were node-positive and 68.2% palpable
–in control arm: 32.4% node-pos and all were palpable (similar proportions of palpable cancers in each group were node-positive)
–1005 women died from breast cancer during the 25 years (1.1%), including 29.4% with diagnosis during the screening period
–25-yr survival 77.1% for women with tumors <2cm and 54.7% if >2cm
–25-yr survival 70.6% for women with mammog-detected cancer and 62.8% in control arm
no diff in 25-yr survival in those with palpable breast ca (66.3% vs 62.8%)
–and, those nonpalpable mammog-identified tumors had 25-yr survival of 79.6%
–for all-cause mortality, 9477 (10.6%) died in followup period, no diff between mammog and control arms
–breast-cancer specific deaths (1005), no diff between mammog and control arms
–361 breast cancer deaths during the screening period: 25-yr survival similar between groups if died from breast cancer during the screening period. and hazard ratio remained similar if screening period extended to 6 or 7 years
no diff in hazard ratio if look at women initially aged 40-49 (1.09, nonsignif) or 50-59 (1.02, nonsignif)
–so, calculated over-diagnosis: excess of  142 cancers in mammog group (666 vs 524), and this excess remained constant 15 yrs after enrollment and represents 22% of all screen-detected invasive cancer – ie, 22% of women who had mammo as screen were found to have an “invasive cancer” by pathologic exam, got treated aggressively, but would not have died from breast cancer. and they can say this because there was such a long followup period and the excess deaths remained constant after 15 ys. this overdiagnosis rate suggests that there is one over-diagnosed breast cancer for every 424 women who had mammog in this trial!!!

so….. this follows recent emails/blogs suggesting the poor performance of mammog screening. one issue is that some of the reason for lack of efficacy of screening is that there is better therapy (works better, less offensive). but one could argue (though i have not seen mentioned in this debate) that breast cancer therapy is still pretty miserable (and expensive) and that even though mortality is not affected, would be much better for the woman to have a little procedure and mild therapy than much more aggressive therapy later. then, of course, the counterarguments that we are medicalizing women more, treating many women who would never get cancer (though we are unable to identify which they are), creating lots of distress, exposing them to radiation. (by the way, as the editorialist notes, the data here on screening efficacy and over-diagnosis is akin to the data for prostate screening in men!!). also, this study was only a 5 year annual screen, not the much more aggressive protocols we use (USPSTF did downgrade to biennial screen age 50-74, with 40-49 offered in special cases)

my own practice has evolved over the past 1-2 years to passively discourage women age 40-49 to screen (ie, if a woman wants it, will screen, but i will add that there is potential harm of radiation exposure and there are no clear clinical data of benefit), and in the 50-70 year range, encourage women to do screening every other year (less radiation, fewer false positives, pretty similar pick-up rates).

geoff

Primary Care Corner with Dr. Geoffrey Modest: Risk and benefit estimates of mammography screening

3 Feb, 14 | by EBM

i posted this in december, but wanted to update the 3rd item below by H Gilbert Welch (the NY times editorial) by giving the formal article/citation which appeared in Dec 30th issue of JAMA Internal Medicine (see  doi:10.1001/jamainternmed.2013.13635) , with a presentation/quantification of the benefits (avoiding advanced breast cancer and cancer deaths) and the harms (false alarms, overdiagnosis, and unnecessary treatment). the following is the conclusion of their mathematical modeling, using low and high estimates from the actual studies, expressed as per 1000 women screened annually for 10 years in women initially aged 40, 50, or 60.

 

40 yo women:     benefits — 0.1-1.6 women will avoid dying from breast cancer;

harms — 510-690 women will have at last 1 “false alarm” with 60-80 getting a biopsy;

??-11 women will be overdiagnosed and treated needlessly with surgery, XRT, chemo

 

50 yo women:     benefits — 0.3-3.2 women will avoid dying from breast cancer;

harms — 490-670 women will have at last 1 “false alarm” with 70-100 getting a biopsy;

3-14 women will be overdiagnosed and treated needlessly with surgery, XRT, chemo

 

60 yo women:      benefits — 0.5-4.9 women will avoid dying from breast cancer

harms — 390-540 women will have at last 1 “false alarm” with 50-70 getting a biopsy;

6-20 women will be overdiagnosed and treated needlessly with surgery, XRT, chemo

 

here is the rest of the december email, fyi.  i would also add that the above harms does not include the potential carcinogenesis from repeated radiation exposure by mammogram, then getting additional views if there is any concern with the mammogram, etc.

 

geoff

 

 

 

 

1. The US preventive service taskforce (USPSTF) just released their guidelines for BRCA testing (see http://www.uspreventiveservicestaskforce.org/uspstf12/brcatest/brcatestfinalrs.htm). in brief, they suggest:

 

–estimated prevalence of BRCA1 or 2  is 0.2% to 0.3% (ie, 1 in 300-500 women) in the general population of women, 6.0% in women with cancer onset before age 40 years, and 2.1% in the general population of Ashkenazi Jewish women. In a meta-analysis of studies in which recruitment was based on family history of breast or ovarian cancer, BRCA1 mutation prevalence was 13.6%, BRCA2 mutation prevalence was 7.9%, and prevalence of either mutation was 19.8%.

–A woman’s risk for breast cancer increases to 45% to 65% by age 70 years if there are clinically significant mutations in either BRCA gene. Mutations in the BRCA1 gene increase ovarian cancer risk to 39% by age 70 years, and BRCA2 mutations increase ovarian cancer risk to 10% to 17% by age 70 years.

–USPSTF recommends that primary care providers screen women who have family members with breast, ovarian, tubal, or peritoneal cancer with 1 of several screening tools designed to identify a family history that may be associated with an increased risk for potentially harmful mutations in breast cancer susceptibility genes (BRCA1 or BRCA2). Women with positive screening results should receive genetic counseling and, if indicated after counseling, BRCA testing. (B recommendation).  one of the simplest tools is below (they list several in their guidelines, though note that the Gail model is not designed for BRCA testing/risk assessment):

 

Did any of your first-degree relatives have breast or ovarian cancer?
Did any of your relatives have bilateral breast cancer?
Did any man in your family have breast cancer?
Did any woman in your family have breast and ovarian cancer?
Did any woman in your family have breast cancer before age 50 y?
Do you have 2 or more relatives with breast and/orovarian cancer?
Do you have 2 or more relatives with breast and/or bowel cancer?

One positive response initiates referral.

–The USPSTF recommends against routine genetic counseling or BRCA testing for women whose family history is not associated with an increased risk for potentially harmful mutations in the BRCA1or BRCA2 genes. (D recommendation)

 

2. USPSTF also recently came out with recommendations about medication use to reduce risk of development of breast cancer in high risk women (see http://www.uspreventiveservicestaskforce.org/uspstf13/breastcanmeds/breastcanmedsrs.htm, ). here are their conclusions:

 

— adequate evidence exists that treatment with tamoxifen or raloxifene can significantly reduce the relative risk (RR) for invasive ER-positive breast cancer in postmenopausal women who are at increased risk for breast cancer

–tamoxifen and raloxifene, in a systematic review, reduced the incidence of invasive breast cancer by 7 to 9 events per 1000 women over 5 years; tamoxifen reduced breast cancer incidence more than raloxifene. Tamoxifen also reduces the incidence of invasive breast cancer in premenopausal women who are at increased risk.

–women with an estimated 5-year risk of 3% or greater (basically using the Gail model) should be considered for treatment.  see their figures 1-4, which display benefit-risk of using tamoxifen vs raloxifene  in 4 subgroups at different risk levels — nonhispanic white women with and without uterus, and similarly for black women.

–the benefits of tamoxifen and raloxifene for breast cancer risk reduction are no greater than small in women who are not at increased risk for the disease. (a bit convoluted: basically, not use meds if woman not at increased risk)

–In addition to breast cancer risk reduction, the USPSTF found adequate evidence that tamoxifen and raloxifene reduce the risk for nonvertebral or vertebral fractures, respectively, in postmenopausal women.

–BUT, tamoxifen and raloxifene increase risk for venous thromboembolic events (VTEs) by 4 to 7 events per 1000 women over 5 years and that tamoxifen increases risk more than raloxifene. the potential harms from thromboembolic events are small to moderate, with increased potential for harms in older women.

— tamoxifen but not raloxifene increases risk for endometrial cancer (4 more cases per 1000 women — and i might add that these are typically more aggressive cancers). Potential harms from tamoxifen-related endometrial cancer are small to moderate and depend on hysterectomy status and age. The potential risks for tamoxifen-related harms are higher in women older than 50 years and in women with a uterus. Tamoxifen may also increase the incidence of cataracts.

–Vasomotor symptoms (hot flashes) are a common adverse effect of both medications that is not typically classified as serious, but these symptoms may affect a patient’s quality of life and willingness to use or adhere to these medications.

–so, their conclusions are that there is moderate certainty that there is a moderate net benefit from use of tamoxifen and raloxifene to reduce the incidence of invasive breast cancer in women who are at increased risk for the disease, and with moderate certainty that the potential harms of tamoxifen and raloxifene outweigh the potential benefits for breast cancer risk reduction in women who are not at increased risk for the disease.

 

 

3. an editorial in the NY times today by H. Gilbert Welch (http://www.nytimes.com/2013/12/30/opinion/breast-cancer-screenings-what-we-still-dont-know.html?(inl=todaysheadlines&emc=edit_th_20131230&_r=0) highlighted several issues about mammography, with the following statistics.  for one thousand 50yo women screened yearly for 10 years (with range from low to high estimates, based on studies):

–490-670 will have a false positive test

–3-14 will be overdiagnosed (ie, diagnosed with cancer, getting therapy, but having a “cancer” which would never have caused a problem: ie, leading to overtreatment)

–but only 0.3-3.2 will avoid a breast cancer death

 

so,

–mammography is a pretty rotten screening test, with high numbers of false positives and overtreatment, and small numbers of “lives saved”. note that the estimates by Welch are for annual mammograms for ten years in women over age 50, and not annual from age 50-75 as typically recommended, or even 40-75 as is often done.

–one very intriguing comment by Welch is that perhaps much of the apparent benefit of screening may be subsumed by the improvement in treatments (ie, does screening continue to be beneficial if treatment is much more effective and better tolerated than before? perhaps screening really adds nothing now since the new and earlier treatments are more effective? remember that the above benefits for treatment in Gilbert’s article are based on old studies prior to current therapies).  i would add here that more aggressive screening of very high risk patients (eg BRCA’s, as above) and other high risk as determined by Gail model (using prophylactic tamoxifen/raloxifene as above) would also likely undercut the benefit of mammography further.

–BUT, mammography is what we have now, and above considerations (which i think are important) are not adequately studied to result in a shift in current screening recommendations. the only change i have made in my practice as a result of recent studies is to offer women at age 50 the option of screening every 2 years, which (per the annals of intl medicine article i sent out several months ago) is associated with fewer false positives and little impact on true positives. i also do screening mammograms on women from 40-50 if they so desire, though i indicate that screening is quite controversial (similar to my approach on PSA screening — shared decision-making).

–and, unfortunately, none of these guidelines focus on the most important issue: breast cancer results from an accumulation of pathologic mutations over decades, and that the likelihood is quite high (in my opinion) that industrial and environmental toxins play an important role here. given the huge numbers of untested toxins currently used, and given the large number introduced into industry yearly that are never tested for potential carcinogenesis, probably the single most important preventative strategy is to focus on widespread testing of chemicals used, which often make it into the environment or the food chain — a proposal which is consistently rebuffed by industry and their governmental lobbies.

 

geoff

Primary Care Corner with Dr. Geoffrey Modest: Mammography, US Task Force on BRCA testing

2 Jan, 14 | by EBM

1. The US preventive service taskforce (USPSTF) just released their guidelines for BRCA testing (see http://www.uspreventiveservicestaskforce.org/uspstf12/brcatest/brcatestfinalrs.htm). in brief, they suggest:

 

–estimated prevalence of BRCA1 or 2  is 0.2% to 0.3% (ie, 1 in 300-500 women) in the general population of women, 6.0% in women with cancer onset before age 40 years, and 2.1% in the general population of Ashkenazi Jewish women. In a meta-analysis of studies in which recruitment was based on family history of breast or ovarian cancer, BRCA1 mutation prevalence was 13.6%, BRCA2 mutation prevalence was 7.9%, and prevalence of either mutation was 19.8%.

–A woman’s risk for breast cancer increases to 45% to 65% by age 70 years if there are clinically significant mutations in either BRCA gene. Mutations in the BRCA1 gene increase ovarian cancer risk to 39% by age 70 years, and BRCA2 mutations increase ovarian cancer risk to 10% to 17% by age 70 years.

–USPSTF recommends that primary care providers screen women who have family members with breast, ovarian, tubal, or peritoneal cancer with 1 of several screening tools designed to identify a family history that may be associated with an increased risk for potentially harmful mutations in breast cancer susceptibility genes (BRCA1 or BRCA2). Women with positive screening results should receive genetic counseling and, if indicated after counseling, BRCA testing. (B recommendation).  one of the simplest tools is below (they list several in their guidelines, though note that the Gail model is not designed for BRCA testing/risk assessment):

 

Did any of your first-degree relatives have breast or ovarian cancer?
Did any of your relatives have bilateral breast cancer?
Did any man in your family have breast cancer?
Did any woman in your family have breast and ovarian cancer?
Did any woman in your family have breast cancer before age 50 y?
Do you have 2 or more relatives with breast and/orovarian cancer?
Do you have 2 or more relatives with breast and/or bowel cancer?

One positive response initiates referral.

–The USPSTF recommends against routine genetic counseling or BRCA testing for women whose family history is not associated with an increased risk for potentially harmful mutations in the BRCA1or BRCA2 genes. (D recommendation)

 

2. USPSTF also recently came out with recommendations about medication use to reduce risk of development of breast cancer in high risk women (see http://www.uspreventiveservicestaskforce.org/uspstf13/breastcanmeds/breastcanmedsrs.htm). here are there conclusions:

 

— adequate evidence exists that treatment with tamoxifen or raloxifene can significantly reduce the relative risk (RR) for invasive ER-positive breast cancer in postmenopausal women who are at increased risk for breast cancer

–tamoxifen and raloxifene, in a systematic review, reduced the incidence of invasive breast cancer by 7 to 9 events per 1000 women over 5 years; tamoxifen reduced breast cancer incidence more than raloxifene. Tamoxifen also reduces the incidence of invasive breast cancer in premenopausal women who are at increased risk.

–women with an estimated 5-year risk of 3% or greater (basically using the Gail model) should be considered for treatment.  see their figures 1-4, which display benefit-risk of using tamoxifen vs raloxifene  in 4 subgroups at different risk levels — nonhispanic white women with and without uterus, and similarly for black women.

–the benefits of tamoxifen and raloxifene for breast cancer risk reduction are no greater than small in women who are not at increased risk for the disease. (a bit convoluted: basically, not use meds if woman not at increased risk)

–In addition to breast cancer risk reduction, the USPSTF found adequate evidence that tamoxifen and raloxifene reduce the risk for nonvertebral or vertebral fractures, respectively, in postmenopausal women.

–BUT, tamoxifen and raloxifene increase risk for venous thromboembolic events (VTEs) by 4 to 7 events per 1000 women over 5 years and that tamoxifen increases risk more than raloxifene. the potential harms from thromboembolic events are small to moderate, with increased potential for harms in older women.

— tamoxifen but not raloxifene increases risk for endometrial cancer (4 more cases per 1000 women — and i might add that these are typically more aggressive cancers). Potential harms from tamoxifen-related endometrial cancer are small to moderate and depend on hysterectomy status and age. The potential risks for tamoxifen-related harms are higher in women older than 50 years and in women with a uterus. Tamoxifen may also increase the incidence of cataracts.

–Vasomotor symptoms (hot flashes) are a common adverse effect of both medications that is not typically classified as serious, but these symptoms may affect a patient’s quality of life and willingness to use or adhere to these medications.

–so, their conclusions are that there is moderate certainty that there is a moderate net benefit from use of tamoxifen and raloxifene to reduce the incidence of invasive breast cancer in women who are at increased risk for the disease, and with moderate certainty that the potential harms of tamoxifen and raloxifene outweigh the potential benefits for breast cancer risk reduction in women who are not at increased risk for the disease.

 

 

3. an editorial in the NY times this week by H. Gilbert Welch (http://www.nytimes.com/2013/12/30/opinion/breast-cancer-screenings-what-we-still-dont-know.html?(inl=todaysheadlines&emc=edit_th_20131230&_r=0) highlighted several issues about mammography, with the following statistics.  for one thousand 50yo women screened yearly for 10 years (with range from low to high estimates, based on studies):

–490-670 will have a false positive test

–3-14 will be overdiagnosed (ie, diagnosed with cancer, getting therapy, but having a “cancer” which would never have caused a problem: ie, leading to overtreatment)

–but only 0.3-3.2 will avoid a breast cancer death

 

so,

–mammography is a pretty rotten screening test, with high numbers of false positives and overtreatment, and small numbers of “lives saved”. note that the estimates by Welch are for annual mammograms for ten years in women over age 50, and not annual from age 50-75 as typically recommended, or even 40-75 as is often done.

–one very intriguing comment by Welch is that perhaps much of the apparent benefit of screening may be subsumed by the improvement in treatments (ie, does screening continue to be beneficial if treatment is much more effective and better tolerated than before? perhaps screening really adds nothing now since the new and earlier treatments are more effective? remember that the above benefits for treatment in Gilbert’s article are based on old studies prior to current therapies).  i would add here that more aggressive screening of very high risk patients (eg BRCA’s, as above) and other high risk as determined by Gail model (using prophylactic tamoxifen/raloxifene as above) would also likely undercut the benefit of mammography further.

–BUT, mammography is what we have now, and above considerations (which i think are important) are not adequately studied to result in a shift in current screening recommendations. the only change i have made in my practice as a result of recent studies is to offer women at age 50 the option of screening every 2 years, which (per the annals of intl medicine article i sent out several months ago) is associated with fewer false positives and little impact on true positives. i also do screening mammograms on women from 40-50 if they so desire, though i indicate that screening is quite controversial (similar to my approach on PSA screening — shared decision-making).

–and, unfortunately, none of these guidelines focus on the most important issue: breast cancer results from an accumulation of pathologic mutations over decades, and that the likelihood is quite high (in my opinion) that industrial and environmental toxins play an important role here. given the huge numbers of untested toxins currently used, and given the large number introduced into industry yearly that are never tested for potential carcinogenesis, probably the single most important preventative strategy is to focus on widespread testing of chemicals used, which often make it into the environment or the food chain — a proposal which is consistently rebuffed by industry and their governmental lobbies.

 

geoff

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