Annual Screening with Breast Ultrasound or MRI Could Benefit Some Women

Results of a large-scale clinical trial presented presented at the 95th Scientific Assembly and Annual Meeting of the Radiological Society of North America (RSNA) provide the first strong evidence of the benefit of annual screening ultrasound for women with dense breasts who are at elevated risk for breast cancer. In addition, the study confirmed that MRI is highly sensitive in depicting early breast cancer.

"We found that annual screening with ultrasound in addition to mammography significantly improves the detection of early breast cancer," said lead researcher Wendie A. Berg, M.D., Ph.D., breast imaging specialist at American Radiology Services, Johns Hopkins — Green Spring Station in Lutherville, Md., "and that significantly more early breast cancer can be found when MRI is performed, even after combined screening with both ultrasound and mammography. However, both ultrasound and MRI increase the risk of false-positive findings."

Women who are at high risk for breast cancer need to begin screening at a younger age, because they often develop cancer earlier than women at average risk. However, women below age 50 are more likely to have dense breast tissue, which can limit the effectiveness of mammography as a screening tool.

Multicenter trials have shown that MRI enables radiologists to accurately identify tumors missed by mammography and ultrasound. The American Cancer Society recommends that some groups of women with a high risk of developing breast cancer should be screened with MRI in addition to their yearly mammogram beginning at age 30. However, MRI is not for everyone.

"Because MRI is a very expensive test and requires intravenous contrast, it is something we only recommend for screening the approximately 2% of women who are known or likely carriers of BRCA1 or BRCA2 gene mutations or have other unusual circumstances that put them at very high risk for breast cancer," Dr. Berg said.

"There are another 10 to 15% of women who are at some increased risk because of personal history of breast cancer, family history of breast cancer and/or dense breast tissue," she added. "For many of these women, MRI is not currently justified, but annual ultrasound would be appropriate in addition to mammography."

Fig 1. This breast MRI showing focus of enhancement in left breast, negative on mammography and screening ultrasound. Pathology proven infiltrating ductal carcinoma

The researchers studied 612 women, mean age 55 years, at elevated risk of breast cancer enrolled at 14 sites in the American College of Radiology Imaging Network (ACRIN) 6666 trial funded by the Avon Foundation and the National Cancer Institute. Women underwent baseline screening mammography and ultrasound with follow-up exams at 12 and 24 months and then a single, contrast-enhanced MRI at 24 months.

Sixteen women were diagnosed with breast cancer. Twelve of the cancers were invasive, and four were ductal carcinoma in situ (DCIS). Over the course of the study, 50 to 56 percent of cancers were shown on mammography. Adding ultrasound allowed detection of 70 to 94% of cancers. Adding MRI allowed for detection of additional cancers at their earliest stage.

Fig 2. Ultrasound showing 9-mm benign mass (arrows) in upper inner quadrant

The study also found that supplemental screening with ultrasound or MRI significantly increased the risk of false-positive findings, leading to unnecessary biopsies in some women.

"It is important that women are advised of the increased potential of undergoing an unnecessary biopsy as a result of screening with ultrasound or MRI," Dr. Berg said, "but we hope this study motivates women and their doctors to learn more about their risk factors and to consider supplemental screening in addition to mammography where indicated."

Also see Abstracts:
Supplemental Yield and Performance Characteristics of Screening MRI after Combined Ultrasound and Mammography: ACRIN* 6666 *American College of Radiology Imaging Network.

Olaparib Induces Tumor Response as Single Agent in BRCA-Deficient Breast Cancer

A small, Phase II international multi-center study data presented during the 45th annual meeting of the American Society of Clinical Oncology (ASCO) for novel, oral anti-cancer treatment olaparib (AZD2281 / KU-0059436), demonstrate it is effective and well tolerated in women carrying the BRCA1 or BRCA2 gene mutation with advanced ovarian or breast cancer.

The study has been selected for inclusion in the ‘Best of ASCO’ scientific program and reports that more than a third of women with BRCA1 or BRCA2 mutations and advanced breast cancer that persisted despite prior treatment experienced tumor shrinkage after receiving the investigational PARP inhibitor olaparib.

Inhibition of PARP, short for poly [ADP-ribose] polymerases, is being explored as a new therapeutic approach in cancers with impaired DNA repair pathways, one example of which is cancers with BRCA deficiency.

Different cancers
Olaparib is a novel, potent inhibitor of poly [ADP-ribose] polymerases PARP-1 and PARP-2 that, in addition to undergoing clinical trials for the development of the treatment of BRCA1 and BCRA2-defective breast cancer, is being trialed in ovarian, pancreatic and colorectal tumors and melanoma. This targeted drug therapy candidate has the potential for use as a single agent or in combination with platinum-based DNA-damaging agents and cytotoxic drugs, as well as radiotherapy. Preliminary data supports the safety and oral bioavailability of the compound and warrant its further development as a potential clinical candidate in cancer therapy.

Hopeful News
About 8% of breast cancer cases are triggered by genetic factors. Although many of the exact causes remain unknown, defects on the BRCA-1 and BRCA-2 genes put women at much higher risk of developing aggressive cancers of the breast or ovaries. Increasingly women testing positive for BRCA1 or BECA2 mutations opt for drastic measures such as elective mastectomy as a precaution because they have an 80% risk of developing breast cancer.

Scientists feel that the preliminary results with olaparib may therefore represent good news. If the results of these first tests are to be believed, the new drug candidate may help thousands of women suffering from genetic breast cancer look for less extreme, targeted drug therapies.

Commenting on the results, lead author, Dr Andrew Tutt, MB ChB, PhD, director of the Breakthrough Breast Cancer Research Unit at Kings College in London, United Kingdom, confirms: “The findings of our study provide very promising evidence that the potent PARP inhibitor olaparib may be useful for treating BRCA-deficient breast cancers. However, this drug is in a very early stage of development, and additional clinical trials are necessary to determine the best way to use olaparib in women with BRCA-deficient breast cancer. We are actively discussing the design of future PARP inhibitor studies for women with BRCA1 and BRCA2 mutations.”

This study, which was carried out at hospitals in Britain, Europe, the United States and Australia, is the first to evaluate olaparib when used alone in women with BRCA-deficient breast cancer. A prior Phase II study showed that some women with BRCA-deficient ovarian cancers responded to olaparib. Tumors that arise in patients with BRCA mutations have a defect in their ability to repair DNA. By adding olaparib, the tumor cells are deprived of another DNA repair mechanism. It is thought that this added inhibition of DNA repair with olaprib then leads to cancer cell death.

Tutt and his colleagues examined the response rate to olaparib (as evidenced by tumor shrinkage) in 54 women with breast cancer that was deficient in BRCA1 or BRCA2 and that persisted despite several rounds of standard chemotherapy. An encouraging forty-one percent of the 27 evaluable patients responded to olaparib (experienced tumor shrinkage) at the higher, 400 mg , of the two doses used in the study. In one patient, the tumor seemed to have disappears completely. Furthermore, a 5.7 month progression free survival was noted

A phase I trial identified 400 mg bd as the maximum tolerated dose (MTD) with an initial signal of efficacy in BRCA-deficient ovarian cancers (ASCO 2008; abst 5510). The researchers in this trial concluded that olaparib at 400 mg 100mg monotherapy twice a day in women with advanced breast cancer was well tolerated, with the most common side effects being mild fatigue, nausea and vomiting.

“These encouraging data demonstrate the potential for olaparib to make a significant impact on the outcomes of patients with BRCA-deficient breast and ovarian cancer. AstraZeneca is fully evaluating the development of this drug in these diseases, and is exploring its potential in other populations of patients with cancers associated with defective DNA repair,” explained Alan Barge, Vice President and Head for Oncology and Infection at AstraZeneca, the manufacturer of the new drug.

A second study conducted in women with advanced ovarian cancer also showed encouraging activity, with objective responses observed in about one third of the women receiving olaparib 400mg monotherapy.

Safety and toxicity
Olaparib is highly active in advanced chemotherapy-refractory BRCA-deficient breast cancer. Toxicity in BRCA and BRCA2 carriers was similar to that reported previously in non-carriers. This first study in BRCA-deficient breast cancers provides positive proof-of-concept for high activity and tolerability of a genetically defined targeted therapy.

Rewarding results
These early, non comparative studies provide optimism about the role of PARP inhibition in certain cancers with DNA repair deficiency. Comments Tutt: “It is rewarding to see our earlier laboratory findings, showing that PARP inhibitors such as olaparib specifically kill BRCA-deficient cells, now seem to be holding true for our patients in the clinic. We are hopeful that olaparib could provide a targeted treatment for women with BRCA-deficient breast cancer.”

Olaparib was originally developed by the UK biotechnology company KuDOS Pharmaceuticals, which has been a wholly owned subsidiary of AstraZeneca since 2006.

ASCO 2009 Abstract:

• Audeh MW, Penson RT, Friedlander M, Powell B, et al. Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer. J Clin Oncol 27:15s, 2009 (suppl; abstr 5500).
• Tutt A, Robson M, Garber JE, Domchek S, et al. Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer. Abstract CRA501 presented at the 2009 American Society of Clinical Oncology annual meeting (ASCO) 29 May-2 June 2009; Orlando, Florida.
• Fong DS, Boss DS, Carden CP, Roelvink M, et al. AZD2281 (KU-0059436), a PARP (poly ADP-ribose polymerase) inhibitor with single agent anticancer activity in patients with BRCA deficient ovarian cancer: Results from a phase I study. J Clin Oncol 26: 2008 (May 20 suppl; abstr 5510)

Journal of Clinical Oncology (ASCO Post Meeting edition):

• Audeh MW, Penson RT, Friedlander M. et al. Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer. Journal of Clinical Oncology, 2009 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 27, No 15S (May 20 Supplement), 2009: 5500.

For more information, read these PubMed abstracts:

• Virag L and Szabo C. The therapeutic potential of Poly(ADP-Ribose)Polymerase Inhibitors. Pharm Rev. 2002; 54:375-429.
• Welcsh PL and King MC. BRCA1 and BRCA2 and the genetics of breast and ovarian cancer. Hum Mol Genet. 2001; 10:705-13.

More information:

• European Medicines Agency (EMEA) Pre-authorisation Evaluation of Medicines for Human Use. Public summary of positive opinion for orphan designation of olaparib for the treatment of ovarian cancer.

Clinical Trials:

• Efficacy and Safety of Olaparib in Pretreated Patients With Measurable Colorectal Cancer, Stratified by Microsatellite Instability (MSI) Status. (NCT00912743)

Photos courtesy of the American Society of Clinical Oncology.