BB&T Contributing Writer

WASHINGTON – Over one third of the members of the American Society of Breast Surgeons (ASBS; Columbia, Maryland) attended their 12th annual meeting held here just a week after cherry blossom time and during the Royal Wedding. Coincidentally, being that the meeting was in our nation's capital, every state had two registrants attending the meeting with the exception of only one from Idaho, almost mimicking Senate representation. Eighty-eight percent of the attendees were surgeons with the majority of their practices dedicated almost 100% to breast surgery alone. This highly interactive conference focused on all aspects of breast cancer prevention, treatments and diagnosis, emphasizing less invasive or more personalized protocols. Several new findings in various aspects of the most common cancer in women have the potential to change current protocol.

Breast surgery has progressively become a specialization for a niche surgery that, unlike other surgical specialties, is often non-hospital based and the surgeon manages the entire spectrum of breast disease. “Modern breast surgeons provide more than operative care for women with breast disease. They are involved in the prevention, diagnosis, and treatment in a specialty that has becoming more precise and individualized. A detailed understanding is critical to improved outcomes and survival rates,“ said Deanna Attai, MD, chair, communications Committee and bard of directors for ASBS, also director, Center for Breast Care (Burbank, California).

Table 1

Ablative Technologies for Breast Cancer Treatment

Source: Industry sources, presentations at ASBS, Biomedical Business & Technology

The general session “What's New in Breast Cancer Surgery,“ a section on percutaneous ablation was presented by V. Suzanne Klimberg, MD, professor of surgery and pathology, University of Arkansas (Little Rock, Arkansas). She said that the three most common modalities studied for in situ ablation have been cryoablation, laser ablation, and radio frequency ablation (RFA). (See Table 1) “While the first one uses cold to destroy the tumor, the other two use heat. “The benefits of using ablation (over excision) are lower cost, decreased side effects and increased cosmesis,“ she said. “The risks associated with ablation are temporary 'mass effect' on mammogram, occasional incomplete ablation of the whole tumor, and the loss of having banked tissue. In tumors that are under 1.5 cm, you can easily get a 1 cm margin and 50% of the time you can remove the whole tumor at biopsy,“ she continued. Over that size either excision or total ablation is required. She then described a small study of 15 patients where they received RF ablation of their tumor bed following lumpectomy. The intent was to ablate 1 cm into the surface of the tumor bed to reduce (or eliminate) local recurrence. For patients who don't want or can't receive radiation, she urged audience members to join an open registry currently in progress to use this novel approach for ablating the tumor bed after lumpectomy in order to reduce local recurrence. In her small study, although standard of care options were offered to all patients, those who did not receive radiation therapy had the same recurrence rate and outcome as those who chose RF ablation of the tumor bed. “This may be a paradigm shift for treating lumpectomy beds, especially for patients over 70,“ she concluded.

David Brenin, MD, University of Virginia Health System (Charlottesville, Virginia) presented the two different transcutaneous technologies as being the only truly non-invasive methods to ablate tumors; albeit the small blade-width incision used by the other ablation modalities can hardly be called invasive. “The goal of transcutaneous ablation is to be able to treat small breast cancers in a brief outpatient procedure using local anesthesia and having a local cancer control rate of 95% with good cosmesis 90% of the time. Since breast conserving surgery (BCS), also called lumpectomy, meets these criteria frequently, and is currently the gold standard, the bar has been set very high for further improvements,“ said Brenin. There are two types of transcutaneous technologies: focused microwave thermotherapy (FMT) and high intensity focused ultrasound (HIFU). Four clinical trials have studied focused microwave thermotherapy using the Celsion (Columbia, Maryland) device according to Dr. Brenin and in one of the trials, 92 patients from several centers had their tumors ablated using focused microwave thermotherapy under ultrasound guidance. No positive margins were found compared to 10% with surgical excision; however, some patients complained of pain during the procedure.

While the majority of the studies using focused ultrasound were performed in China, Brenin shared a U.S. study of 22 patients who had their tumors ablated using ultrasound guided HIFU. At 55 months, 2 out of the 22 (9%) had a local recurrence and 80% had a negative biopsy at 6 months. The configuration of the focused ultrasound equipment used for that study was designed to treat tumors of the bone, fibroids, and other areas of the body and was used under ultrasound guidance. Brenin felt that if a unit was designed specifically for breast, and utilized MR guidance, that both the results and the length of time to treat could be drastically improved. InSightec (Dallas) has submitted a trial design to the FDA to begin a clinical study on 30 patients and once those are completed with good results, follow with an additional 220 patients.

The only ablation devices that currently have FDA clearance for treating benign tumors of the breast, called fibroadenomas, is the laser ablation by Novian Health (Chicago) and two cryoablation companies Sanarus Medical (Pleasanton, California), who was not present, and IceCure (Casearea, Israel) who received clearance December 2010 and was launching their product for the first time here at the meeting. IceCure has a second-generation device compared to the original Sanarus system in respect to three major aspects: more user friendly, three ways to control the device, and the ability to freeze all the way to the tip of the probe. Since cryoablation of fibroadenomas is intended to be an office procedure, it is imperative that the physician be able to operate the unit independently and without assistance. Physicians must hold the ice probe in one hand and the handheld ultrasound sensor in the other hand, leaving no hand free to control the machine. IceCure allows their device to be operated by a foot pedal, the probe handpiece, or the touchpad; the first two methods eliminate the need for an assistant.

A third cryotherapy company, CryoFem (San Diego), is an early stage company seeking funding for commercialization. While not exhibiting, they had representatives present to discuss their innovative device. CryoFem is striving to be a third generation device in that they have developed a single phase rechargeable self-contained system that will not require tanks of liquid nitrogen, making the unit much smaller, lighter and portable from room to room. They also claim that they can create more lethal ice, allowing them to be able to treat larger tumors, based upon studies performed to date. Besides complete tumor ablation, they are also developing a balloon for intraoperative cryoablation of the tumor bed following lumpectomy that will compete with both intraoperative radiation as well as intraoperative RF ablation. Although this is a long-term proposition, the recently discovered immune effect following cryoablation provides the potential to leapfrog other ablation technologies.

Vitamin D for prevention

A growing body of evidence already suggests that a vitamin D deficiency may play a causative role in breast cancer development. In addition to increasing the odds of acquiring breast cancer by over two-fold, new findings suggest that vitamin D deficiency may also lead to more aggressive breast tumors once diagnosed. This new research was presented by Kristin Skinner, MD, University of Rochester Medical Center (Rochester, New York) and the Roswell Park Cancer Institute (Buffalo, New York). The study examined 155 women who underwent surgery for breast cancer and were monitored for their vitamin D levels. Patients with low vitamin D levels had more invasive tumors and a higher recurrence rate than those patients with adequate vitamin D. “This study shows that low vitamin D levels correlated with numerous factors that are associated with poor breast cancer outcomes. Based on these results, doctors should strongly consider monitoring vitamin D levels among breast cancer patients and correcting them as needed,“ said Luke Peppone, PhD, from the same center.

Lengthen observation for recurrence in certain patients

Researchers at Hoag Memorial Hospital Presbyterian (Newport Beach, California) found that while women treated with radiation following breast-conserving surgery had a significantly lower recurrence rate, those radiated patients experienced a more invasive recurrence when they did, and at a much longer time interval. “This is the first study to focus on the pattern of recurrence in DCIS (ductal carcinoma in situ) patients treated with lumpectomy,“ said investigator Janie Wen Grumley, MD. “Radiation therapy accompanying wide local excision (lumpectomy) of DCIS is known to reduce local cancer recurrence by 50 percent. But when the cancer does come back, we found major differences in the recurrence pattern between patients who did and did not receive radiation,“ she continued. This ten-year study followed 1,000 patients with DCIS who underwent breast-conserving surgery with or without radiation. DCIS is an early and highly curable form of cancer and often the tumors are treated by excision only of the diseased portion of the breast. Surgery may be accompanied by radiation treatment to kill ay cancer cells that remain. Since excision alone is common in DCIS patients, it was not unusual that of these 1000 patients, 26% opted for mastectomy, 39% for excision plus radiation therapy, and 35% for excision alone. The study found that radiated patients took about twice as long to recur and had a more invasive recurrence. This resulted in a small but statistically significant lower breast cancer survival rate. “Overall, far fewer patients receiving radiation for DCIS have cancer recurrences. However, this study demonstrates that for a statistically significant number of these women, a five-year cancer-free status is not a landmark,“ said Grumley.

Selection of appropriate additional screening tool

Finding cancers when they are small saves lives, and patients who are at a higher risk for developing breast cancer need more than just an annual mammogram. In a breakfast workshop, titled “Breast Screening: Who Gets What—Mammography, Ultrasound, MRI“; Wendie Berg, MD, PhD, Magee-Womens Hospital, University of Pittsburgh School of Medicine (Pittsburgh) discussed the evolving guidelines and evidence for supplemental screening of women at increased risk. She emphasized that there are a lot of risk assessment models to choose from, but she felt that the Tyrer-Cuzick model was one of the most accurate of all models available. Patients with 25% or greater lifetime risk of developing breast cancer should begin screening at age 30. While MR imaging has been the typical addition to mammography, Berg pointed out that in the multicenter Avon Foundation (New York)-funded ACRIN 6666 trial that Berg led, 26% of patients who underwent MR imaging as an adjunct needed a recall on first look, and another 14% were recommended for short term follow-up that is often not covered by insurance. Because of the false positives, high cost, and relatively poor patient tolerance of MR imaging, other imaging modalities have been entering the arena for screening to supplement mammography. The difficultly for physicians in adding an additional imaging component to the screening mammogram is to decide which of the many available is best for that specific patient. Below are the results of analysis that Berg presented, along with her comment “These numbers are compared to film-screen mammography for most of these comparisons, though for ultrasound we know this also holds compared to digital mammography.“ (See Table 2)

Table 2

Possible Tests to Add to Mammography

Source: Wendie Berg, MD, at American Society of Breast Surgeons annual meeting

Dense breasts require additional screening

Patients with an intermediate risk of 15%-20% include women with dense breasts, which represent 30%-50% of the screening population. Effective in late 2009, Connecticut was the first state to mandate communication of breast density to patients; requiring patient reports to include information about breast density based on BI-RADS density measurements established by the ACR. If patients are notified their breast tissue is dense, they must also be informed that they could benefit from supplementary screening tests and have those tests paid for. Other states, including New York and California also are looking at passing similar laws. Berg noted that ultrasound was the cheapest and easiest to perform but with a very low reimbursement rate that leaves little incentive for physicians to do it. Many times the additional imaging is not covered by insurance, so cost becomes an issue for patients. MR imaging is 10 times more costly than ultrasound or mammography and is time consuming for the patient, which becomes another consideration in selecting that modality. SonoCine (Reno, Nevada) developed an automated whole breast ultrasound screening device that can be attached to any manufacturer's ultrasound system while both U-Systems (Sunnyvale, California) and Siemens-Acuson (Washington) have dedicated ultrasound breast volume scanners. The approximate 20 minutes it takes to screen a whole breast can be managed by a staff member, freeing the doctor for just the reading of the films that can be done in about 5 minutes depending on the size of the breast. U-Systems just completed a $6.5 million funding round from existing investors and their affiliates. Delphinus Medical Technologies (Plymouth, Minnesota) are finalizing an ultrasound tomography unit that scans the entire breast in 1 minute and produces MR-like images using both transmission and standard reflection ultrasound. Used in addition to mammography, ultrasound can detect seven cancers out of every 1000 patients screened, as opposed to mammography alone that detects 3.5 out of every 1000 patients screened. Data from the ACRIN 6666 Study presented at RSNA 2009, but not yet published, demonstrated that adding screening ultrasound to routine mammography increased the detection of cancer by 29% over mammography alone.

Single Dose Radiation Therapy

In breast intraoperative radiotherapy (IORT), the entire dose of radiation is delivered with a single high dose fraction immediately after excision of the tumor. An IORT treatment can be delivered in as little as 8 minutes, compared to the seven-week course of external beam therapy or the 6 day, twice daily, regimen for accelerated partial breast irradiation (APBI). IORT, although cleared by the FDA in 1999, is used infrequently in the U.S. but is on the verge of becoming more mainstream; while approximately 53% of early cancers are treated with it in Europe. The international randomized TARGIT Trial started accrual in 2000 to determine if there is noninferiority between the technique using IORT and conventional external beam radiotherapy (EBRT) in women with early, low-risk breast cancer suitable for breast conservation as primary treatment. The main outcome measure is risk of local relapse within the treated breast.

Several papers presented here provided some insight into the findings of the TARGIT trial. One looked at the difference in cosmetic outcome and found that the cosmetic effects of targeted radiotherapy are significantly improved compared to those obtained with conventional EBRT, particularly 1 year after surgery. In a general session on intraoperative radiation therapy, Roberto Orecchia, MD, Professor of Radiation Oncology at the University of Milan (Milan, Italy) presented the Italian experience and found, similar to other studies, that the local failure rate was the same with IORT as it was with conventional radiation treatment. He concluded, “IORT can be proposed as a standard treatment alternative to whole breast irradiation.“ In another presentation, Jayant Vaidya, MD, PhD, Memorial Sloan Kettering (New York) found that the timeliness of the delivery of radiation increased its effectiveness; that the sooner the radiation (intraoperatively) the lower the recurrence rate. He measured and compared cytokines in the wound fluid in the tumor cavity after excision and again after radiation of the same cavity. He found that about 2/3 of the cytokines were killed by the radiation and hypothesized that these cytokines left in the wound for days prior to conventional radiation treatment could be acting as nutrients for any cancer cells lurking behind in the tumor bed. His study demonstrated that there was no difficulty in interpreting later mammograms (an initial concern), similar outcomes, less pain and increased patient satisfaction using IORT. In addition, he presented a financial calculation showing that IORT saves $6000 per patient and concluded “There is a $1.4 billion cost to the U.S. economy if we do not use IORT.“

Currently three companies offer a form of IORT although the TARGIT trial utilizes the Carl Zeiss (Jena, Germany) Intrabeam device. Xoft (Sunnyvale, California), now owned by ICAD (Nashua, New Hampshire) utilizes a miniaturized X-ray source and IntraOp Mobetron (Sunnyvale, California) has a mobile electron linear accelerator IORT system.