The sound of success – advantages and challenges of ultrasound

Rates of breast cancer are increasing across the globe. With nearly 1.7 million new cases in 2012 - and around 2.1 million expected by 2030 - it is the most common cancer in women, accounting for around 25% of all female cancer diagnoses.

Within the developed world, the scale of the problem is well known, and screening programmes are widely implemented. In the UK, women between 50 and 70 years old are invited to receive regular mammograms; in the US, some women start as early as 40. With the lifetime breast cancer risk as high as one in eight, diagnosis is a major point of focus.

The developing world, however, is quite another story. While breast cancer is often discussed as a disease of affluent countries - tied in to lifestyle factors, an ageing population and the use of hormone replacement therapy - in fact, nearly half of cases occur in less-developed nations. More jarringly, these parts of the world account for 58% of breast cancer deaths, a disproportionate figure suggesting less-than-exemplary detection programmes and treatment.

Across many low and middle-income countries, breast cancer is typically diagnosed very late, leading to a bleak prognosis. Many countries simply do not have the resources for population-based mammography screening, which can be complex and costly to get off the ground. This means that the search is on for alternatives. And while mammography is still the only screening programme that has been shown to be effective, a number of researchers are turning their attention to a different contender: ultrasound.

True or false?

According to a recent study, published in December 2015 in the Journal of the National Cancer Institute, cancer detection with ultrasound is comparable with mammography in effectiveness. In countries lacking a strong healthcare infrastructure, therefore, ultrasound screening might be a viable option.

"Many countries do not perform screening, and breast cancer incidence is increasing globally. Ultrasound can be done with very low-cost equipment, and portably, in remote areas," explains lead researcher Dr Wendie Berg, professor of radiology at the University of Pittsburgh School of Medicine.

Deeply concerned by the limitations of mammography - particularly in women with dense breasts - Berg has a longstanding interest in improving methods of early detection for breast cancer. These efforts were further spurred by her own cancer diagnosis, in which the tumour was only visible on an MRI scan.

Between 2004 and 2006, she chaired the American College of Radiology Imaging Network's (ACRIN's) 'ACRIN 6666' study, a large multicentre, randomised and controlled trial of screening ultrasound in the US, Canada and Argentina.

This study enrolled 2,662 women, all of whom had dense breasts alongside at least one other risk factor for breast cancer. The participants received physician-performed ultrasound as well as mammography (digital or film screen), every year for three years, and the two sets of data were interpreted independently. They then received a biopsy or 12-month follow-up.

In the first instance, the researchers wanted to compare ultrasound and mammography combined screening with mammography taken alone. They determined that although ultrasound and mammography combined yielded a higher rate of false positives, it detected an additional 4.2 cancers per 1,000 women screened. This suggests that combining the two can be a highly effective strategy, with a low interval cancer rate.

"I first became interested in breast ultrasound over 20 years ago, when ultrasound-guided core biopsy first became available," says Berg. "Ultrasound equipment had recently improved a lot, and I was surprised by how much could be seen with it. We have always performed ultrasound to evaluate lumps. About 15 years ago, many of us pushed for a study to look at ultrasound as a supplement to mammography to screen asymptomatic women who have dense breasts. That became the 'ACRIN 6666' study."

Generally speaking, ultrasound is not considered appropriate for breast cancer screening, because its specificity is relatively poor. While it will flag up many abnormalities, most of these won't be cancerous, increasing the risk that a perfectly healthy woman will receive an unnecessary and invasive biopsy. Instead, it is currently used as a supplemental test when abnormalities are identified. If a mammogram or physical exam locates a specific area of concern, an ultrasound can be used to determine whether the lump is solid (such as a benign or cancerous tumour) or fluid-filled (such as a cyst).

Before using it as a primary screening tool, you would need to weigh up the additional sensitivity - which is particularly pertinent in the case of women with dense breasts - against the rate of false positives incurred.

"We have long known that ultrasound is very good at seeing masses that we don't see on mammography, for example palpable cysts or cancers," says Berg. "Because ultrasound is not limited by tissue density, it sees many masses that are not seen on mammography. Most of those masses are not cancer."

In effect, this means that in countries where mammograms are widely available and similarly priced to ultrasound, ultrasonography is unlikely to become the gold standard as a population-wide screening tool. However, for women with dense breasts, not to mention lower-income countries, it seems clear that ultrasound bears further analysis.

Cross-comparison

Berg's latest study returned to 'ACRIN 6666', this time asking how ultrasound might work as a primary screening tool for breast cancer. The researchers sifted through the data to determine how mammograms compare with ultrasound taken alone.

"We had previously reported in JAMA 2012 that the primary goal of our study was successful: that adding ultrasound to mammography improved detection of invasive breast cancer," she explains. "Because of our study design and the growing international problem with breast cancer, we decided to also consider our data as if ultrasound were the only screening option and see how it compared with mammography."

The results were eye-opening. As might have been expected, the overall specificity of ultrasound was lower than that of mammography, and those with extremely dense breasts were most likely to suffer false positives (a trend not seen with mammograms). However, of the 111 breast cancers suffered by the study cohort, mammography managed to identify 59 and ultrasound 58. What's more, the cancers detected by ultrasound were more likely to be node-negative and invasive - capable of spreading to the rest of the body and killing a patient. 53 of the ultrasound-detected cancers were invasive, versus 41 of those detected through mammography.

Mammography outshone ultrasound in terms of identifying ductal carcinoma in situ (DCIS), but this is the earliest possible form of breast cancer, which is not in itself life-threatening and, which, in many cases, does not progress.

The study authors did express caution about their findings, noting that a larger study would be needed to support the contention that ultrasound is more sensitive to invasive cancers. Additionally, they felt that their study might slightly underestimate cancer detection by mammography: only 41.8% of the scans were performed digitally, and since these women had dense breasts, they were perhaps less suited to mammography than the general population.

The fact remains, however, that the rates of cancer detection were very similar. The authors concluded that ultrasound should be seen as a supplemental test for women with dense breasts, particularly where MRI is not appropriate.

"Where mammography is already widespread, adding the use of ultrasound will help find more cancers. It is time that we routinely offer this to women with dense breasts as a choice. Where mammography is not available, ultrasound certainly warrants further evaluation," says Berg.

She believes that in countries lacking organised screening programmes, ultrasound could hold a lot of potential. Along with several other researchers, she is working to develop low-cost portable ultrasound with computer-assisted detection and diagnosis, which might assist these efforts.

After all, for many women in developing countries, the choice does not lie between screening mammography and screening ultrasound: it lies between screening ultrasound and nothing at all. If ultrasound initiatives prove cheap and easy to implement, there is little doubt that lives will be saved in the process.

"It is time to do prospective studies using ultrasound screening where there is no existing mammography. This is starting to be done in some Asian and developing countries," says Berg. "It is easy to guide needle biopsy with ultrasound, and ultrasound does not expose the patient to any ionising radiation. Invasive breast cancers are usually well seen on ultrasound, and ultrasound is much more comfortable for the patient than mammography."

Over the decades ahead, as developing countries adopt more Westernised lifestyles, breast cancer rates are expected to surge. With the need for population-wide early detection becoming more salient than ever, ultrasound screening could well be what it takes to identify sufferers in time.