Breast Cancer Research - Latest Comments

Overdiagnosis!!!

italo nenci — 2012-01-03T11:21:22Z

Your results provide clear evidence for the high level of overdiagnosis with consequent overtreatment due to mammographic screening: Thank you:
Italo Nenci, Professor of Pathology

Are MDA-MB435 cells mammary carcinoma cells or melanoma cells?

Ulrich Pfeffer — 2011-11-08T16:27:42Z

Holliday and Speirs discuss in their illuminating review on breast cancer cell lines as models for breast cancer research the cell line MDA-MB435, which has been considered as a breast cancer cell line until reports on their potential origin from a human melanoma (see ref. in Holliday and Speirs). More recent evidence shows that i) MDA-MB435 are indeed identical to M14 melanoma cells, ii) M14 were derived from a male melanoma patient but carry two X-chromosomes whereas MDA-MB435 were derived from a female patient (Chambers, Cancer Res. 2009, 5292; Hohestelle and Schutte, Cancer Res. 2009, 7893) and iii) 18% of human breast cancers express melan-A and other melanoma markers (Bachmeier et al. Int J Oncol. 2008, 1011). MDA-MB435 cells are therefore most likely breast cancer cells.

Vitamin D deficiency may contribute to cause of death for those diagnosed with breast cancer

William B. Grant — 2011-07-01T10:49:46Z

The paper by Patnaik et al. [1] is quite interesting. The conclusion, “Comorbid conditions contribute importantly to both total mortality and breast cancer-specific mortality among breast cancer survivors. Attention to reducing the risk of cardiovascular disease should be a priority for the long-term care of women following the diagnosis and treatment of breast cancer.” is correct, although other cancers, COPD, and diabetes should also be added to the list of diseases to be concerned about.

Missing from the paper, however, is any mention of how to go about reducing the risk of cardiovascular disease (CVD) or any other disease. A rather simple and straight forward approach is available: increase serum 25-hydroxyvitamin D [25(OH)D] levels. There is excellent evidence from ecological [2,3] and observational studies [4-7] that vitamin D deficiency is an important risk factor for breast cancer and other types of cancer [2,3,6]. The discrepancy between case-control and nested case-control studies of breast cancer incidence with respect to serum 25(OH)D level is due to the decrease of the prognostic value of a single serum 25(OH)D level value with increasing time [7,8].

There is also very good observational evidence that vitamin D deficiency is an important risk factor for CVD incidence [9-11] and death [12]. Vitamin D deficiency has also been implicated in COPD [13,14] and diabetes [9,15].

While admittedly these associations have not been confirmed in randomized controlled trials except for all-cancer incidence [16], and not everyone is convinced of the health benefits of vitamin D [17], if the findings are substantially correct, then increasing serum 25(OH)D levels to above 40-45 ng/ml would be the simplest thing that could increase survival after diagnosis of breast cancer [18]. In fact, an 11.6-year follow-up study of those diagnosed with breast cancer in Toronto found a hazard ratio = 1.73 (95% CI, 1.05 to 2.86) for all-cause mortality rate for those with serum 25(OH)D levels <20 ng/ml compared to >30 ng/ml [19]. The Endocrine Society recently released vitamin D guidelines above those recommended by the Institute of Medicine [20]. While additional evidence may be required to fully assess the role of vitamin D in reducing the burden of disease, waiting to change policies on vitamin D the five plus years it will take for results of such studies as VITAL to be announced [21] will very likely subject many people to needless suffering and premature death, including African-Americans, who are more likely than white-Americans to have vitamin D deficiency [22]. There are very few risks associated with increasing serum 25(OH)D levels to 100 ng/ml [23].

References
1. Patnaik JL, Byers T, DiGuiseppi C, Dabelea D, Denberg TD. Cardiovascular disease competes with breast cancer as the leading cause of death for older females diagnosed with breast cancer: a retrospective cohort study. Breast Cancer Research 2011, 13:R64 (20 June 2011) epub
2. Grant WB, Garland CF. The association of solar ultraviolet B (UVB) with reducing risk of cancer: multifactorial ecologic analysis of geographic variation in age-adjusted cancer mortality rates. Anticancer Res. 2006;26:2687-99.
3. Grant WB. Lower vitamin-D production from solar ultraviolet-B irradiance may explain some differences in cancer survival rates. J Natl Med Assoc. 2006;98:357-64.
4. Abbas S, Linseisen J, Slanger T, Kropp S, Mutschelknauss E, Flesch-Janys D, Chang-Claude J. Serum 25-hydroxyvitamin D and risk of postmenopausal breast cancer - results of a large case-control study. Carcinogenesis. 2008;29:93-9.
5. Abbas S, Chang-Claude J, Linseisen J. Plasma 25-hydroxyvitamin D and premenopausal breast cancer risk in a German case-control study. Int J Cancer. 2009;124:250-5.
6. Gandini S, Boniol M, Haukka J, Byrnes G, Cox B, Sneyd MJ, Mullie P, Autier P. Meta-analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma. Int J Cancer. 2011;128:1414-24.
7. Grant WB. Effect of interval between serum draw and follow-up period on relative risk of cancer incidence with respect to 25-hydroxyvitamin D level; implications for meta-analyses and setting vitamin D guidelines, Dermato-Dermatology, 2011 July, Aug Sept.;3(3) epub
8. Robien K, Cutler GJ, Lazovich D. Vitamin D intake and breast cancer risk in postmenopausal women: the Iowa Women's Health Study. Cancer Causes Control. 2007;18:775-82.
9. Parker J, Hashmi O, Dutton D, Mavrodaris A, Stranges S, Kandala NB, Clarke A, Franco OH. Levels of vitamin D and cardiometabolic disorders: systematic review and meta-analysis. Maturitas. 2010;65:225-36.
10. Anderson JL, May HT, Horne BD, Bair TL, Hall NL, Carlquist JF, Lappé DL, Muhlestein JB; Intermountain Heart Collaborative (IHC) Study Group. Relation of vitamin D deficiency to cardiovascular risk factors, disease status, and incident events in a general healthcare population. Am J Cardiol. 2010;106:963-8.
11. Lee JH, Gadi R, Spertus JA, Tang F, O'Keefe JH. Prevalence of vitamin d deficiency in patients with acute myocardial infarction. Am J Cardiol. 2011;107:1636-8.
12. Fiscella K, Franks P. Vitamin D, race, and cardiovascular mortality: findings from a national US sample. Ann Fam Med. 2010;8:11-8.
13. Franco CB, Paz-Filho G, Gomes PE, Nascimento VB, Kulak CA, Boguszewski CL, Borba VZ. Chronic obstructive pulmonary disease is associated with osteoporosis and low levels of vitamin D. Osteoporos Int. 2009;20:1881-7.
14. Janssens W, Mathieu C, Boonen S, Decramer M. Vitamin D deficiency and chronic obstructive pulmonary disease: a vicious circle. Vitam Horm. 2011;86:379-99.
15. Boucher BJ. Vitamin D insufficiency and diabetes risks. Curr Drug Targets. 2011;12:61-87.
16. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007;85:1586-91.
17. Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones G, Kovacs CS, Mayne ST, Rosen CJ, Shapses SA. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011;96:53-8.
18. Grant WB. In defense of the sun: An estimate of changes in mortality rates in the United States if mean serum 25-hydroxyvitamin D levels were raised to 45 ng/mL by solar ultraviolet-B irradiance. Dermato-Endocrinology, 2009;1:207-14.
19. Goodwin PJ, Ennis M, Pritchard KI, Koo J, Hood N. Prognostic effects of 25-hydroxyvitamin D levels in early breast cancer. J Clin Oncol. 2009;27:3757-63.
20, Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM. Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab, July 2011, Jun 6. [Epub ahead of print]
21. Manson JE. Vitamin D and the heart: why we need large-scale clinical trials. Cleve Clin J Med. 2010;77:903-10.
22. Grant WB. Peiris AN. Possible role of serum 25-hydroxyvitamin D in Black–White health disparities in the United States. J Am Med Directors Assoc. 2010;11:617-28.
23. Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. Am J Clin Nutr. 2007;85:6-18.

The follow-up time was too long to find a correlation

William B. Grant — 2011-07-01T10:48:41Z

Breast cancer is characterized by rapidly growing tumors. For example, diagnoses are more common in spring and fall due to solar UVB and vitamin D reducing risk in summer and melatonin in winter (1). Thus, it should not be expected that a single serum 25(OH)D level measurement would have good prognostic value several years later. Indeed, a review of case-control and nested case-control studies of breast cancer incidence with respect to serum 25(OH)D level found that follow-up periods less than three years resulted in significant inverse correlations, while studies with longer follow-up periods did not (2).

In a nested case-control study of breast cancer incidence with respect to oral vitamin D intake, the relative risk of cancer decreased with increasing follow-up time: 0.66 (95% CI, 0.46–0.94) for follow-up periods of 0–5 years, 0.73 (95% CI, 0.53–1.01) for 5–10 years, 0.99 (95% CI, 0.74–1.32) for 10–15 years, and 1.23 (95% CI, 0.86–1.75) for more than 15 years (3).

Thus, for breast cancer, case-control studies or nested case-control studies with very short follow-up times are required to show the inverse correlation between vitamin D and incidence rates, so the results of this study do not contradict the UVB-vitamin D-cancer hypothesis.

References

1. Oh EY, Ansell C, Nawaz H, Yang CH, Wood PA, Hrushesky WJ. Global breast cancer seasonality. Breast Cancer Res Treat. 2010 Aug;123(1):233-43.
2. Grant WB. Effect of interval between serum draw and follow-up period on relative risk of cancer incidence with respect to 25-hydroxyvitamin D level; implications for meta-analyses and setting vitamin D guidelines, Dermato- Endocrinology, July/August/September 2011 July, Aug Sept.;3(3) epub
http://www.landesbioscience.com/journals/dermatoendocrinology/article/15364/
3. Robien K, Cutler GJ, Lazovich D. Vitamin D intake and breast cancer risk in postmenopausal women: the Iowa Women's Health Study. Cancer Causes Control. 2007 Sep;18(7):775-82.

Cases description

Mikko Vuorela — 2011-05-19T10:16:16Z

It would very important to know how many of the 454 cases actually had ovarian cancer and how many had breast cancer. Now there is only short description of family histories.

Acknowledgement

Elizabeth O'Flynn — 2011-04-20T14:53:39Z

Parametric images produced using Magnetic Resonance Imaging Workbench(MRIW) software (Institute of Cancer Research, London, United Kingdom)(1) by Dr Maria Schmidt and Mr Marco Borri.

1. d'Arcy J, Collins D, Padhani A, Walker-Samuel S, Suckling J, LeachM: informatics in radiology (infoRAD): magnetic resonance imaging workbench: analysis and visualisation of dynamic contrast-enhanced MR imaging data. Radiographics 2006;26(2):621-32.

In defence of peer review

Dorothy Bishop — 2011-01-04T10:28:16Z

Richard Smith seems not only to underestimate the benefits of peer review, but also to misrepresent its function, at least in the context of journal publishing. Thus he states that the process determines “which papers will be published…” etc. Unfortunately, all too often editors relinquish their responsibilities and treat the peer review process as a vote, but this is a distortion of the real function of peer review, which should be to offer advice to the editor and the author.

Of course, Dr Smith is right to point out the arbitrary and unreliable features of peer review, and the lack of hard evidence for its benefits. But most of those who’ve tried to evaluate the system seem to focus just on ‘scores’ given to papers. There should be much more to a review than this. In this regard Dr Smith notes “many can tell of anecdotes of how a study they published was much improved by peer review”, but he then dismisses such evidence as balanced by anecdotes of bad experiences with reviewers. But has anyone attempted to quantify this aspect of peer review, i.e. by asking authors whether, on balance, they think the system improves their manuscripts? Dr Smith noted that when he gave a talk on the topic, most scientists were strongly in favour of peer review. Are they all deluded?

I write this at the end of a week where I have struggled to master a new analytic method, having been convinced by a reviewer that it is relevant to my study. My initial response on receiving the review was the one I usually have: anger at this ignorant fool who hadn’t understood the paper and was wasting my time. But as I struggled to formulate a response, I realised that there was a point to what s/he was saying. I have learned a lot, and the paper has benefited as a result. This is not uncommon, in my experience, especially when I am moving into a new area. I’ve also had reviewers force me to explain my arguments more clearly, to read a literature that I was ignorant of, and to look critically at my assumptions. So this, I think, is the up side of peer review: it stops us from being egocentric and ignoring alternative viewpoints. In the extreme case, reviewers have preserved my reputation by pointing out ignorant errors. Of course, I’ve experienced my fair share of muddled and biased reviewers, but I have to say that in general, I find them outnumbered by reviewers who make an honest attempt to engage with what I’ve written and offer constructive advice. I’d be sorry if this were not available to me. And, yes, I spend time on the other side of the fence, reviewing papers by my ‘peers’, but I don’t regard it as a total waste. Here too, there is benefit in being forced to engage with other people’s ideas.

I do think the real problem is editors, a topic I have blogged on (see http://tinyurl.com/33lzsvp). Increasingly, one sees editors who don’t use any judgement at all, but just keep going back to reviewers until there is agreement. I recently had a journal secretary get very tetchy with me when I refused to re-review a paper where the only recommendations I’d made were minor and could easily have been checked by a competent editor. I doubt that the editor read the paper at all.

Some of Dr Smith’s arguments puzzle me. Why does it cost £100 to review an article, when the reviewers aren’t paid and the process is largely automated? Yes, it can be hard to find reviewers, but this seems an overestimate, once the system is up and running. I started acting as an editor for PLOS One this year, and I usually aim to find 2 reviewers for each paper I handle. It typically takes me about 10-20 minutes per paper. PLOS One also achieves much faster turnaround times than the months cited in Dr Smith’s article, indicating that this can be achieved (though seldom is with medical journals, in my experience).

Dr Smith and I are clearly in agreement about many aspects of science publishing, as might be expected given our mutual involvement in PLOS journals. However, his uniformly negative analysis of peer review cannot go unchallenged.

It is wrong to encourage women to attend breast cancer screening

Paul Pharoah — 2010-11-09T09:45:05Z

The the conclusion made by McCann and colleagues that "women should be encouraged to continue with screening" is not supported by their data. Women should be encouraged to decide for themselves whether the marginal reduction in breast cancer mortality associated with regular mammography is worth the harms. A false positives is an associated harm and if a woman decides that that harm, based on her own experience, outweighs any benefit, she should be encouraged to make the decision not to have screening that is right for her.

The concept that a successful screening programme depends on a high uptake rate needs to be revisited. The benefits and harms of mammography are individual based and uptake rates are of no consequence to a woman who decides to undergo mammography or not. It is inappropriate to define the success of the programme is defined in population terms.

PREDICT prognostication tool now available online

David Greenberg — 2010-09-08T12:50:48Z

The new web-based prognostication and treatment benefit tool for early breast cancer in the UK referred to in the conclusions of this paper is now freely accessible online at
http://www.predict.nhs.uk/

No proven correlation

Dene Godfrey — 2010-02-18T15:22:32Z

The review states:

"Any increase in the disproportionality of breast cancer in the upper outer quadrant would be inconsistent with an explanation relating to the greater amount of target epithelial tissue in that region but does parallel the increasing use of cosmetics in the underarm area [2-5]."

All four references are to studies/reviews by this author and do not appear to be directly related to any market information on the increase in use of underarm products. There does not, therefore, appear to be any tangible evidence to support the author's assertion that there is specifically a parallel increase in both use of underarm products and cancer in the upper outer quadrant. Unless specific market information is quoted on any increase in underarm product volumes used, this statement remains purely speculative and, therefore, any correlation, parallel or otherwise, should surely not be claimed.