Moderate Alcohol Intake and Cancer Incidence in Women

Published this week in the Journal of the National Cancer Institute, and available to members on the RCRBG website, is the revelation from the Million Women Study, that any alcohol is 'bad' alcohol, as regards breast cancer risk.

Valerie Beral's team at Oxford demonstrated that increasing but moderate alcohol consumption in women was determined to be associated with an increased risk of cancers of the oral cavity and pharynx, esophagus, larynx, rectum, breast, and liver, and with a decreased risk for thyroid cancer, non–Hodgkin lymphoma, and renal cell carcinoma. No differences in cancer risks were observed between drinkers of wine only and other consumers of alcohol

As ever, this could be seen as a scare story, but has to be taken in context with some of the other proven beneficial effects - eg a glass of red wine and its protective effects against heart disease.
If you are a woman who is at increased risk already from family history or a prior biopsy of atypia, maybe you are the one who needs to be aware of this finding and consider modifying your lifestyle.

In the greater scheme of things, everything has risks and benefits - look at HRT use itself, which was the original target of this research

RECIST criteria for tumour volume measurement for trials

The first, formal revision of specific guidelines, known as RECIST (Response Evaluation Criteria in Solid Tumours), used by clinicians to measure tumour size and response to treatment, has been published January 20 in a special issue of the European Journal of Cancer
European Journal of Cancer
Volume 45, Issue 2, January 2009

The only proven way of measuring tumour response is by measuring size on imaging. This of course is subject to measurement error, and so criteria have been published that allow measurement of response in even small tumours (5mm)

When it comes to clinical trials of therapeutic agents, tumour shrinkage (objective response) and time to the development of disease progression are both important endpoints in trials, and, increasingly in recent years, trials have been using time to progression (or progression-free survival) as their main endpoint on which to base conclusions about the efficacy of a drug.

The new RECIST (RECIST 1.1 to distinguish them from the original RECIST) answer some of the questions and issues that have arisen since 2000 as a result of changing methodologies and available treatments

Key changes in RECIST 1.1 that will simplify, optimise and standardise the assessment of tumour burden in clinical trials are as follows:

1. A reduction in the number of lesions to be assessed for response from a maximum of ten to five, and from five to a maximum of two per organ
2. New guidance on making robust measurements of lymph node involvement
3. Confirmation of response is required for trials with objective response as a primary endpoint, but is no longer required for randomised studies, since the control arm of these studies provides appropriate means for interpreting results of the experimental arm
4. The definition of disease progression has been refined so that it not only includes a 20% increase in the size of the lesion, but also a 5 mm absolute increase as well, so that changes of just a few mms in very small tumours, which may be within the range of measurement error, are not unnecessarily described as disease progression
5. Guidance on imaging, including its use in the detection of new lesions and the interpretation of FDG-PET scan assessment

Rising incidence of cancer in survivors

Rising incidence of breast cancer among female cancer survivors: implications for surveillance
Paper in this months British Journal of Cancer, British Journal of Cancer (2009) 100, 77 – 81 from the Netherlands, showing a marked rise in breast cancer incidence among female cancer survivors.

There are certainly questions raised from this study, in contradistinction to recent papers suggesting that most patients who are not in trials or undergoing adjuvant therapy can be discharged after surgery.

What implications will it have on your Cancer Centre's policy?

Do some screen-detected breast cancers spontaneously regress?

An article in this weeks Archives of Internal Medicine from the Norwegian Screening Programme, discuss how there is an excess of cancers in the screened population, and how some of these regress spontaneously

Arch Intern Med. 2008;168(21):2311-2316

it appears that some breast cancers detected by repeated mammographic screening would not persist to be detectable by a single mammogram at the end of 6 years. This raises the possibility that the natural course of some screen-detected invasive breast cancers is to spontaneously regress

News from the Fall meeting of ACRIN at the Pentagon

The Fall meeting of ACRIN was held last week at Pentagon City in DC.



Of note was the report from UCSF-led ACRIN study, on the use of breast MRI in the assessment of neoadjuvant chemotherapy -

"MRI is superior to mammography for evaluating the response to neoadjuvant chemotherapy for breast cancer, according to the early results of a trial from the University of California, San Francisco (UCSF) and nine other academic centers in the U.S. The results were presented at last week's American College of Radiology Imaging Network (ACRIN) fall meeting".

The study was developed under ACRIN's protocol 6657, representing the imaging side of the larger I-SPY (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis) trial aimed at gauging breast cancer treatment response. Sponsored by the Cancer and Leukemia Group B Foundation (CALGB), the I-SPY trial is "testing imaging and tissue-based biomarkers in combination, predicting neoadjuvant response to standard chemotherapy," explained Nola Hylton, Ph.D., a principal investigator from UCSF who discussed the results.

Participants were scanned four times during chemotherapy, including once pretherapeutically, once after the first cycle of chemotherapy, and a third time between the anthracycline and Taxol agents. A fourth scan prior to surgery was intended to detect residual disease and evaluate the post-treatment sensitivity and specificity of MRI. Mammography scans were acquired to coincide with the first and last MRI scans

MRI measurements included morpholgic measurements of the tumors classified according to BI-RADS criteria for breast MRI, including tumor diameter measurements. "We're also measuring by computer the volume of the tumor and the microvascular parameters of the tumor, PE [percent enhancement] and SER [signal enhancement ratio]," used to distinguish malignant tissue, said Hylton.

he investigational software assesses tumor volume quantitatively based on functional rather than anatomic criteria, she explained. "We are measuring something that is based on how these tumors enhance, and assigning [volume] based on an algorithm calling it part of the tumor or not. So it's really a virtual volume [that defines] areas of the image based on function, in this case how the tumors enhance."

The investigators acquired one T1-weighted precontrast and two T2-weighted postcontrast scans, "and from that we looked at the early ratio of enhancement from the early time point to the late time point," she said. This calculation yields the signal enhancement ratio, which distinguishes tumor from nontumor. Another protocol ensures that the direction of diameter measurements remains constant over the course of multiple imaging exams

At the end of surgery, 43% of the patients were complete responders, 38% were partial responders, and 10% demonstrated stable disease. "There were a larger portion of complete responders among those who also received Taxol," she said. "And there were a total of 82 pathologic complete responders, meaning that there was no invasive disease left at pathology. Sixty percent of patients had a complete solid lesion, and 32% had two identifiable lesions in the breast.

Compliance with the study was surprisingly good, especially considering the complexity of the protocol, requiring both biopsy and multiple imaging exams in addition to treatment, she said. In addition, lesion morphology was very similar to a pilot study. There were 36 single masses; 65 multilobulated masses with well-defined margins; 66 lesions with area enhancement, irregular margins, and nodularity; 30 of the same without nodularity; and 19 patients with septal spread.

Once the analysis has been completed, more precise data will be presented at the 2008 RSNA meeting in Chicago.

Researchers Are Investigating Two New Potential Tools for Diagnosing Breast Cancer

Researchers at Jefferson Medical College of Thomas Jefferson University in Philadelphia are investigating contrast-enhanced subharmonic ultrasound as a noninvasive exam that could help physicians make a diagnosis. In subharmonic imaging, pulses are transmitted at one frequency, but only echoes at half that frequency are received

In a study reported in the September 2007 issue of Radiology, researchers tested their technique on 14 women ranging in age from 37 to 66 who had 16 biopsy-proven lesions. The researchers used a GE Logiq 9 ultrasound machine that was modified to perform grayscale subharmonic imaging, transmitting at 4.4 megahertz and receiving at 2.2 megahertz. The women underwent precontrast imaging and imaging using contrast

The researchers’ results using subharmonic imaging were better than conventional ultrasound and mammography. Of the 16 lesions, four were malignant. Mammography had 100% sensitivity and 20% specificity for these lesions. Subharmonic imaging had 75% sensitivity and 83% specificity for the same lesions.

The other tool -
Researchers at Duke University in North Carolina have developed a new scanner that they believe is better at finding early cancers in women than conventional mammography, and it can also be used for diagnosis and monitoring of therapeutic response(s). It is a hybrid between a SPECT and a CT scanner they are collectively calling mammotomography

The researchers have done imaging observer studies using phantoms to compare x-ray digital mammography with CT. “We have been able to show a significant statistical improvement using CT compared to mammography,” Tornai says. “In mammography, you lose a lot of information because you have only a 2D image. With the 3D image that the SPECT/CT scanner produces, lesions become more conspicuous because overlapping tissues are removed. In contrast to x-ray tomosynthesis, a pseudo-3D x-ray imaging modality, the SPECT/CT system produces a uniform 3D image and does not require any breast compression.”

The hybrid scanner that the researchers have built from novel configurations of conventional equipment circles the breast as the patient lies on a specially built table.

The scanner is also able to see areas, including the chest wall, that traditional mammograms may not. They have tested the hybrid scanner extensively with phantoms and has begun successfully scanning subjects with known cancer.

Because SPECT requires IV injection of imaging agents, the SPECT portion of the scanner would not likely be broadly used for routine screening mammography. However, if it proves to be more effective, the hybrid SPECT/CT system might be especially helpful for women who are at high risk for developing breast cancer because of familial history or a genetic predisposition.

Breast SPECT/CT also could be used for women with dense breasts or implants because mammography is known to miss up to 25% of cancers in these women, Tornai says. The scanner and associated imaging procedure also should be less costly to employ than MRI

Potential mechanisms of breast cancer risk associated with mammographic density: hypotheses based on epidemiological evidence

Lisa J Martin; Norman F Boyd
An interesting paper published online in Breast Cancer Res. 2008;10(1) by the above authors
This is reported in a Medline article this week

There is now extensive evidence that mammographic density is a risk factor for breast cancer, independent of other risk factors, and is associated with large relative and attributable risks for the disease. The hypotheses that we have developed from the observations described above are summarized here

Cumulative Exposure to Mammographic Density and Breast Cancer Risk

Mammographic density reflects variations in the tissue composition of the breast, and is associated positively with collagen and epithelial and nonepithelial cells, and negatively with fat. Increasing age, parity, and menopause are all associated with reductions in the epithelial and stromal tissues in the breast, and with an increase in fat. These histological changes are reflected in the radiological appearance of the breast, and are consistent with mammographic density being a marker of susceptibility to breast cancer, in a manner similar to the concept of 'breast tissue age' described in the Pike model. Like breast tissue age, variations in mammographic density may reflect the mitotic activity of breast cells and differences in susceptibility to genetic damage, and cumulative exposure to density may have an important influence on breast cancer incidence.

Mitogens, Mutagens and Mammographic Density

Mammographic density is influenced by some hormones and growth factors, as well as by several hormonal interventions, and is associated with urinary levels of a mutagen. We postulate that the combined effects of cell proliferation (mitogenesis) and genetic damage to proliferating cells by mutagens (mutagenesis) may underlie the increased risk for breast cancer associated with extensive mammographic density. As described above under 'Relationship of mitogenesis and mutagenesis', mitogenesis and mutagenesis are not independent processes. Increased cell proliferation can increase lipid peroxidation, and the products of lipid peroxidation can increase cell proliferation

Potential areas for genetic influence include variation in the regulation of the hormones and growth factors that act on the breast, the response and modelling of breast tissue to these stimuli, and the processes that are involved in oxidative stress and the generation of mutagens.