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SAN FRANCISCO -- Referrals for genetic testing almost doubled in the first 6 months after actress Angelina Jolie announced that she would undergo bilateral mastectomy after testing positive for BRCA1 mutation, according to a study reported here.

The study was one of several summarized during the briefing.

From Jolie's public disclosure in May 2013 to November 2013, 916 women sought genetic testing at Toronto's Sunnybrook Odette Cancer Center. That compared with 487 referrals in the 6 months before the announcement.

The proportion of women who met testing criteria and who had positive tests increased slightly but not significantly, , said during a press briefing that preceded the Breast Cancer Symposium, which begins here today and continues through Saturday.

"Although the number of referrals approximately doubled, the quality of referrals remained the same," he said. "That is, the appropriate (high risk) individuals were referred to the clinic. The referrals made were well justified and not only affected by the media without meeting the criteria."

Two other studies were also highlighted during the briefing:

• Comparing outcomes with unilateral versus double mastectomy showed that both procedures have low complication rates, although certain types of complications occur more often when both breasts are removed.
• An analysis of neoadjuvant chemotherapy for breast cancer showed that the completeness of response and cancer subtype predicted the likelihood of locoregional recurrence.

The 'Angelina Effect'

Disclosed in an opinion piece published in the New York Times, to undergo prophylactic bilateral mastectomy made headlines worldwide. The announcement also led to a "bombardment" of queries for many oncologists, as women wanted to know more about about BRCA testing and whether they should be tested.

Many people, oncologists included, thought the announcement would spark at least a short-lived run on BRCA testing. However, no one had examined the "Angelina effect" in detail, said Raphael. To quantify the effect and determine its persistence, investigators at the Toronto cancer center retrospectively reviewed data from the center's Familial Cancer Program. They compared referrals for BRCA testing in the 6 months before and 6 months after Jolie's public disclosure.

Clinical and demographic characteristics of patients were similar during the two 6-month periods, including age, history of breast and ovarian cancer (including familial history), and the proportion of men.

From November 2012 to May 2013, 487 referrals for genetic testing led to 213 tests (44%) and identification of 29 (6%) carriers of BRCA1/2 mutations. In the 6 months after Jolie's disclosure, the center had 916 referrals (a 90% increase), which led to testing in 437 (48%) cases and identification of BRCA1/2 mutations in 61 (7%) patients.

Raphael and colleagues have begun a follow-up study to examine the "Angelina effect" in the first year after the public disclosure. The 6-month analysis showed a steady increase in referrals for genetic testing, not a spike immediately after Jolie's announcement followed by a tail off in number of referrals, he added.

If the interest in BRCA testing remains high, healthcare providers and payers will be challenged to meet the demand. In the 6 months before Jolie's announcement, the estimated cost associated with referrals was $146,000 and the cost for testing was $213,000. In the 6 months after the announcement, the estimated costs for referrals and testing approximately doubled, consistent with the rise in referrals and tests.

Mastectomy Safety Affirmed

The number of breast cancer patients opting for prophylactic bilateral mastectomy has risen steadily in recent years, despite evidence that removing the unaffected breast does not improve survival. Currently, about 20,000 women undergo bilateral mastectomy each year, said , of NorthShore University HealthSystem in Evanston, Illinois.

In general, modern mastectomy has a good safety profile, but negative effects of bilateral procedures have not been studied extensively, Sisco continued. To examine the issue, investigators analyzed data from the American College of Surgeons (NSQIP). The NSQIP database encompasses 400 hospitals and provides quantitative analysis of 30-day risk-adjusted surgical outcomes.

The analysis included records for 11,727 women who underwent single mastectomy and 6,502 who had bilateral procedures from 2005 to 2012. About 80% of women in the single-mastectomy group had implant-based reconstruction, as did about 90% of women who had double mastectomies.

Overall, women in both groups had low complication rates. Certain types of complications did occur more frequently after bilateral mastectomy: implant loss (0.7% versus 1.0%, P=0.02), reoperation after implant (6.8% versus 7.6%, P=0.05), transfusion after implant reconstruction (0.3% versus 0.8%, P<0.001), and transfusion after tissue reconstruction (3.4% versus 7.9%, P<0.001).

The two groups did not differ with respect to major medical complications, which occurred in fewer than 1% of cases, said Sisco. These included heart attack, pneumonia, kidney failure, stroke, urinary tract infection, and blood clots.

"Complications after mastectomy with reconstruction are infrequent," said Sisco. "Double mastectomy results in more surgical complications than single mastectomy. Women with breast cancer should consider these factors when deciding whether to undergo double mastectomy."

Sorting Out Benefits of Neoadjuvant Therapy

Patients with large but localized breast cancers often receive neoadjuvant chemotherapy to reduce tumor volume prior to surgery or to downstage a tumor so that the patient becomes a candidate for surgery. However, specific predictors of outcome -- particularly locoregional recurrence -- have received little attention and remained unclear.

To identify predictors of outcome after neoadjuvant therapy, investigators in North America and Europe retrospectively analyzed data from 12 randomized clinical trials of neoadjuvant chemotherapy, involving a total of 11,955 patients. The primary objectives were to determine locoregional recurrence rates by pathologic complete response (pCR), tumor subtype, type of surgery (mastectomy or lumpectomy), and clinicopathologic factors, said , of the National Surgical Adjuvant Breast and Bowel Project in Pittsburgh and the University of Florida Cancer Center in Orlando.

The patients had a median follow-up of 5.4 years and median age of 49. Additionally, 61% of the study population had stage T2 tumors and 47% had positive lymph nodes. A multivariable analysis involving 5,252 patients showed an overall locoregional recurrence rate of 8.8%, including 7.8% for women who underwent lumpectomy and 10.4% for those who had mastectomy.

The recurrence rate varied by tumor subtype:

• Hormone receptor (HR)+/HER2 -/grade 1-2: 4.2%
• HR+/HER2-/grade 3: 9.2%
• HR-/HER2+: 14.8%
• HR+/HER2+: 9.7%
• HR-/HER2-: 12.2%

In the multivariable model for lumpectomy, predictors of locoregional recurrence were age <50 (P=0.017), tumor subtype (odds ratios 3.29-7.9, P<0.0001), and pCR (P<0.0001). Investigators analyzed the data by two definitions of residual disease and both showed an increased hazard for recurrence as compared with patients who achieved pCR (hazard ratios 2.36 and 1.46).

Among the patients who underwent mastectomy, only tumor subtype and pCR status predicted locoregional recurrence. The hazard ratios associated with the different tumor subtypes were lower as compared with mastectomy (HR 1.61 to HR 3.51) but remained statistically significant (P<0.0001). Investigators again analyzed the effect of pCR by two different definitions of residual disease, both of which yielded statistically significant hazard ratios (HR 3.88 and 2.29, both P<0.0001).

"Our findings have clinical implications relative to further tailoring the use of adjuvant radiation therapy after neoadjuvant chemotherapy and support the conduct of ongoing clinical trials attempting to tailor locoregional therapy in this setting," Mamounas concluded.

In general, the 5-year rates of locoregional recurrence were low across all subgroups, less than 10% in most cases, he noted.