WASHINGTON, DC - Breast cancers in very high-risk women, especially the 10% to 15% who are triple negative - i.e., negative for estrogen, progesterone, and HER2 - continue to present major challenges for oncologists. Presentations here at the fourth AACR Science of Cancer Health Disparities conference suggest ways to detect and treat breast cancer in these patients in order to optimize their prognosis.

Early breast cancer diagnosis in high-risk uninsured or underinsured women - who are disproportionately younger, African American, and more likely to have triple-negative breast cancer (TNBC) - is improved by magnetic resonance imaging (MRI) screening specifically targeted to this high-risk group, according to a study from Duke University Medical Center.

The study, conducted between 2004 and 2011, compared rates of breast cancer mammography screening in 299 underserved women who had a general risk for breast cancer with the rates for 299 high-risk, underserved women who received combined mammogram and MRI screening.

The average age of women undergoing mammography was 50; the average age of those undergoing MRI was 47. In the general-risk mammography group, 40% of women were African American, 25% were white, 25% were Hispanic, and 1% "other," while in the MRI group the rates were 33%, 62%, 3% Hispanic, and 2% other.

Mammography screening detected one breast cancer, while MRI screening detected nine. The cost per diagnosis was $37,375.00 for MRI, vs $21,561.22 for mammography. The number of benign breast biopsies/total biopsies was seven out of eight (88%) for mammography screening, vs 31 out of 40 (78%) for MRI.

Compliance with follow-up studies was higher for MRI than for mammography screening: 90% vs 75%, and was aided by breast patient navigators recruited at health and screening fairs in North Carolina.

Lead author Anne C. Ford, MD, Assistant Professor of Obstetrics and Gynecology at Duke University Medical Center, said targeted breast MRI screening is cost-effective in this high-risk group because it detects more breast cancers than mammography screening. "If you truly target high-risk women with MRIs, you can find the cancers, and you can find them early," she said.

In this study, a grant helped to lower the cost of breast MRI screening, and Dr. Ford said she hopes the high cost of breast MRI screening will come down with more frequent use.

One of her coauthors on the study, Victoria L. Seewaldt, MD, Professor of Medicine and co-leader of the Breast and Ovarian Cancer Program at Duke, pointed out that only 14% of African American women with TNBC will be alive at one year, and thus early detection is greatly needed.

Warburg Effect Found in Precancerous Cells

The study she reported at the meeting assessed whether activation of biologic pathways that predict aggressive TNBCs are also activated in atypia in high-risk African American women. The researchers used spectroscopy to track glucose metabolism in live mammary epithelial cells from high-risk women. A "glucose addiction" was found in precancerous mammary epithelial cells in African American women, an important finding given that aggressive cancers consume glucose avidly and produce lactic acid, she explained.

This shift toward lactate production, even in the presence of adequate oxygen, is known as the Warburg effect-"a very ancient observation," said Dr. Seewaldt. "This is something that is a hallmark of aggressive cancers; it is something that we can target. We were very excited to find it in precancerous cells."

The Duke team concluded that although the Warburg effect is generally thought to be a late event in breast cancer, in high-risk African American women the effect occurs during cancer initiation. Asked by OT about the clinical significance of these findings in precancerous cells, Dr. Seewaldt said that since the study defined the ability to identify abnormal glucose and activated signaling networks, she hopes the study results ultimately will lead to advances in early detection and prevention in women at an elevated risk for breast cancer.

Determine Subtype

At diagnosis, it is very important to determine the subtype of breast cancer in a high-risk woman, especially whether she has TNBC, several speakers at the AACR meeting emphasized, noting, though that TNBC has a range of histology-"We're talking here about the basal-like subtype," said AACR President Judy E. Garber, MD, MPH, Director of the Center for Cancer Genetics and Prevention at Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School.

If women with TNBC are not cured, "they recur quickly," with metastases tending to go to the liver and brain. "Their biology is really quite different," Dr. Garber noted of women with TNBC. These women are candidates for neoadjuvant chemotherapy, she said, but they have a poor prognosis if the drugs don't produce a pathological response.

Dr. Garber said that platinum chemotherapy is a treatment option for TNBC and HER2 + breast cancer, and can be used as an early agent in metastatic TNBC, especially if there is central nervous system involvement.

Platinum agents can be used for TNBC in combination with an investigational PARP inhibitor in a clinical trial. (PARP inhibitors target poly (ADP-ribose) polymerase, a key enzyme in cell proliferation and DNA repair.)

Dr. Garber cited several promising PARP inhibitors, including olaparib and iniparib. High-risk women whose breast cancer is caused by BRCA1 or BRCA2 mutations appear to be especially responsive to PARP inhibitors, she said.

There are now 129 trials focusing on TNBC listed in the federal government's clinicaltrials.gov database, she noted, some of which are investigating neoadjuvant therapy. These include: carboplatin and eribulin mesylate; sunitinib and carboplatin/paclitaxel; and carboplatin/paclitaxel and the gamma secretase inhibitor RO4929097.

Dr. Garber also cited an ongoing trial of neoadjuvant cisplatin in breast cancer patients with BRCA1 mutations. She said there has been recent interest in treating TNBC patients and HER2 + patients with cisplatin.

Other Research Areas for Clinical Trials

Dr. Garber suggested the following other topics ripe for clinical trials:

* Novel TNBC prevention strategies;

* Novel early-detection strategies;

* Biopsying metastatic lesions to understand chemotherapy resistance or to help choose a targeted therapy;

* Studying circulating tumor cells;

* Investigating how to minimize treatment toxicities;

* Studying how best to treat TNBC metastases to the brain.

Heritable Marker?

As of now, in addition to surgery, "we have to rely on general chemotherapy for TNBC," said Lisa A. Newman, MD, MPH, Director of the Breast Care Center and Professor of Surgery in the Division of Surgical Oncology at the University of Michigan Comprehensive Cancer Center in Ann Arbor.

She warned that recommendations to defer mammography screening until age 50 could have dire consequences for black women, who are more likely to develop high-risk breast cancer at a younger age even when data are adjusted for socioeconomic variables.

"Is African ancestry associated with a heritable marker for high-risk breast cancer subtypes?" asked Dr. Newman, who is participating in a University of Michigan scientific collaboration with Ghana. She noted that women in Ghana tend to develop breast cancer at a younger age, and they have a very high incidence of triple-negative breast cancer.

In Ghana, reproductive history (such as multiple births) does not seem to correlate with TNBC, Dr. Newman said, adding, "We really don't know a lot about what drives these triple-negative tumors."

An earlier study published in Cancer Epidemiology, Biomarkers & Prevention, found that two or more full-term births put African American women at higher risk of hormone receptor-negative breast cancer. However, the increased risk occurred only in women who did not breast-feed. Data came from the Black Women's Health Study, which has followed 59,000 African American women since 1995.

HOUSTON-Tandem use of two monoclonal antibodies that inhibit HER2 may help with drug resistance to trastuzumab, according to speakers here at the "New Roles for the EGFR Family in Cancer" symposium on cancer research at the University of Texas MD Anderson Cancer Center.

Carlos L. Arteaga, MD, Vice Chancellor's Chair in Breast Cancer Research and Director of the VICC Breast Cancer Research Program at Vanderbilt-Ingram Cancer Center, predicted that the standard treatment for HER2 resistance will be dual blockade with monoclonal antibodies using different mechanisms of action.

The data suggest synergy when two monoclonal antibodies are used, he said, describing his ongoing Phase III trial named Cleopatra (Study to Evaluate Pertuzumab + Trastuzumab + Docetaxel vs Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-Positive Metastatic Breast Cancer) of approximately 800 patients with HER2-positive metastatic breast cancer or recurrent locally advanced disease.

Patients are being treated with either trastuzumab and docetaxel, the current gold standard, or with a dual HER2 blockade of trastuzumab, pertuzumab, and docetaxel.

The initial trial results are positive, he said. "How positive I don't know, but my sense is that this study is going to change the landscape in the way we treat patients with metastatic disease with first-line therapy. The standard will become two antibodies plus chemo - that will be the way to go."

He cited a recent randomized Phase III trial by Kimberly Blackwell et al (JCO 2010;28:1124-1130) that tested whether total HER2 blockade with lapatinib plus trastuzumab increased overall survival compared with lapatinib alone in 296 patients with disease progression on or after trastuzumab treatment. Overall survival at six months was 80% for the combination arm versus 70% for the single-agent arm, and 56% and 41%, respectively, at one year.

The implications, Dr. Arteaga said, are that (1) Trastuzumab-resistant tumors respond to lapatinib, suggesting they remain dependent on HER2; (2) Lapatinib and trastuzumab each alone cannot inhibit the output of HER2 to HER3 and PI3K/Akt completely; and (3) Dual HER2 blockade with the two drugs trumps reactivation of HER3 and is superior to lapatinib alone.

He said this would be most effective in the adjuvant or neoadjuvant setting. "Whether they should be used together in combination with chemotherapy in the metastatic setting is more debatable," Dr. Arteaga said, citing cost, toxicity, and the fact that the regimen is not curative.

He concluded by saying that in HER2-positive tumors, dual blockade of the HER2/HER3/PI3K pathway "at the least" is required for maximal therapeutic effect.

Combine Trastuzumab with Pl3K/Src Inhibitors

Another speaker at the meeting, Dihua Yu, MD, PhD, Professor and Deputy Chair of the Department of Molecular and Cellular Oncology at MD Anderson, said that trastuzumab resistance can be overcome by therapies combining trastuzumab with PI3K/Src inhibitors. Trastuzumab dissociates Src from ErbB2 leading to PTEN activation, she said.

"Less than 35% of patients with metastatic breast cancer respond to Herceptin as a single agent," she said, adding that two to five percent of patients suffer severe treatment-related side effects such as cardiac dysfunction.

Citing her own research and that of others, Dr. Yu hypothesized that trastuzumab resistance can result from PTEN-loss or PI3K activation. Overcoming this might be achieved by novel combination therapies targeting PI3K/PTEN pathways. As an example, she said, combined treatment with triciribine and trastuzumab significantly inhibits the growth of PTEN-treated BT474 zenografts.

Thomas Jefferson University Hospital surgeons have found that a carefully selected surgical care check list of 12 measures can reduce Whipple procedure wound infections by nearly 50%.

Stopping smoking at least two weeks prior to surgery, gown and glove change prior to skin closure, and using clippers over razors to shave the surgical area are some of the measures that helped reduce infection rates, according to the study published in the October 26 online issue of the Journal of Surgical Research.

In the retrospective study, Harish Lavu, MD, Assistant Professor, and colleagues analyzed clinical data from 233 consecutive Whipple procedures from October 2005 to May 2008 on patients who underwent routine preoperative preparation (RPP). That preparation is less comprehensive than the 12-measure surgical care bundle-for example, it uses a razor for hair removal and iodine skin preparation and does not include smoking cessation.

Those rates were compared with those for 233 consecutive Whipple procedures performed from May 2008 to May 2010 following the implementation of the surgical care bundle.

There was a 49% reduction in wound infections in the surgical care bundle group (15%) compared with the RPP group (7.7%), a statistically significant difference.

"It is typically quite difficult to achieve a 50 percent reduction in an adverse outcome," Dr. Lavu said in a news release. "We can make a significant impact on lowering wound infection in patients undergoing this surgery by using this set of guidelines."

Wound infection rates for Whipple procedures are historically higher and more common than in other procedures. Infections can be painful and require reopening the incision, which can ultimately leave scarring. Also, if an infection is not identified quickly, it can spread and patients can become very ill.

Two standout measures, Dr. Lavu says, are the gown and glove change prior to skin closure and intraoperative wound edge protection, which separates the edges of the incision from contact with visceral contents, instruments, and gloves during the procedure. And, as past studies have shown, using chlorhexidine-alcohol for skin preparation, instead of iodine, helps lower the risk of wound infections.

"The preoperative and postoperative briefings alone, which are now being instituted in many American hospitals, reduce complications simply by improving communication among members of the health care team," Dr. Lavu says.

While some procedures at certain hospitals include a similar surgical bundle care, Jefferson's is the first one, the researchers believe, that has been implemented for pancreatic surgery.

"Now it is the standard of care here, and we are trying to move the surgical care bundle as it applies to other kinds of surgery, even in other departments at Jefferson," Dr. Lavu says.

The 12 measures that were implemented at Jefferson in 2008 include:

* Absence of remote infection

* Preoperative smoking cessation

* Pre-admission chlorhexidine-alcohol skin preparation

* Preoperative clipper hair removal

* Preoperative chlorhexidine-alcohol skin preparation

* Preoperative antibiotic administration

* Intraoperative wound edge protection

* Intraoperative glycemic control

* Intraoperative temperature control

* Gown and glove change prior to skin closure

* Deep venous thrombosis prophylaxis and beta-blocker administration

* Pre- and post-operative briefings.