WASHINGTON, June 18 — Estrogen receptor-negative breast cancer cells converted to ER-positive status after exposure to trastuzumab (Herceptin), suggesting a new strategy for treating breast cancer, an investigator reported here.

• Explain to patients that a drug used to treat breast cancer carrying the HER2 receptor made cells sensitive to hormonal therapy.
• Emphasize that the findings came from laboratory studies and did not involve treatment of breast cancer patients.
• Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

After three days of exposure to trastuzumab in vitro, the previously ER-negative cells exhibited upregulation of ERα, Gauri Sabnis, PhD, of the University of Maryland in Baltimore, said at the Endocrine Society meeting.

Moreover, trastuzumab-stimulated cells responded to the growth-inhibiting effects of antiestrogens and aromatase inhibitors.

“This strategy may offer a new avenue for treatment of breast cancer patients with ER-negative and HER2-positive tumors,” Dr. Sabnis concluded.

About 25% of breast cancers are ER negative: typically they’re treated with chemotherapy and radiation only, because endocrine therapy usually has no growth-inhibiting activity in such tumors.

In previous studies, Dr. Sabnis and colleagues found that breast cancer cells and tumors resistant to an aromatase inhibitor had reduced levels of ERα and increased levels of HER2.

The aromatase inhibitor-resistant cells had been derived from an ER-positive cell line, leading investigators to examine whether HER2 inhibition would lead to upregulation of ERα in ER-negative, HER2-positive cells.

Dr. Sabnis and colleagues added trastuzumab at a concentration of 50 mcg/mL to ER-negative cells and evaluated ER expression after 72 hours.

Investigators then treated the cells with different concentrations of estradiol and the estradiol precursor androstenedione. The hormones triggered proliferation of the formerly ER-negative cells.

Subsequently, the investigators evaluated the effects of aromatase inhibitors and antiestrogens on trastuzumab-pretreated ER-negative cancer cells.

They observed significant growth inhibition — comparable to what occurs when ER-positive cells are exposed to aromatase inhibitors or antiestrogens.

The inhibition was significantly greater than treatment with an aromatase inhibitor or antiestrogen alone — or with trastuzumab alone.

For example, letrozole (Femara) had an IC₅₀ of 3 nmol, which is similar to the growth inhibiting response the aromatase inhibitor has in ER-positive cells, said Dr. Sabnis.

A literature review uncovered evidence that trastuzumab might also upregulate ERα in humans with ER-negative breast cancer.

Italian investigators gave trastuzumab to 10 patients with HER2-positive, ER-negative breast cancer. Three of the 10 subsequently had upregulation of ERα, and two of the three were treated with letrozole monotherapy and remained progression free for as long as three years (Breast Cancer Res 2006; 8(6): 407).

Moreover, a clinical trial initiated at the University of Michigan in Ann Arbor is evaluating trastuzumab’s ability to induce ER expression in patients with ER-negative, HER2-positive breast cancer.

Dr. Sabnis reported no disclosures. Co-investigator Angela Brodie, PhD, disclosed a financial relationship with Syndax.

Primary source: The Endocrine Society

Source reference:
Sabnis G, Brodie A “Trastuzumab sensitizes ER negative, HER-2 positive breast cancer cells (SKBr-3) to endocrine therapy” ENDO 2009; Abstract OR38-02.

HOUSTON, June 17 — In an international consensus statement described as practice-changing, new treatment guidelines for early-stage breast cancer call for use of systemic therapies on the basis of individual tumor characteristics.

• Explain to patients that new treatment guidelines for early-stage breast cancer call for use of systemic therapies on the basis of individual tumor characteristics.

Treatment decisions should focus on the scientific justification for using endocrine therapy, anti-HER2 treatment, and chemotherapy, authors of the 2009 St Gallen International Expert Consensus concluded in guidelines published online in Annals of Oncology.

Though recognizing the heterogeneous nature of breast cancer, the consensus recommendations call for development of a personalized treatment plan for each patient.

The guidelines include a new treatment algorithm based on advances in knowledge about how to match therapy with tumor characteristics to achieve the best outcomes.

“Because these decisions are based on quite separate criteria, previous attempts to produce a single-risk categorization and a separate therapy recommendation are no longer considered appropriate,” the authors said.

In a prepared statement, panel member Richard Gelber, MD, of Harvard and Dana-Farber Cancer Institute in Boston, said the consensus “further refines the treatment algorithm by identifying ‘thresholds for indication’ of each type of systemic treatment modality based on criteria specific to each modality.

“We expect the refined algorithm to change clinical practice because it clarifies the indications for each treatment modality available today.”

Knowing the specific tumor characteristics is essential for deciding which treatment or combination offers a patient the best chance for success. Consistent with that approach to decision making, the panel set forth some general principles for treatment selection:

• Adjuvant endocrine therapy is recommended for most patients with any detectable level of estrogen receptor (ER).
• Anti-HER2 therapy, currently limited to trastuzumab (Herceptin), is recommended for almost all patients with HER2-positive disease.
• Reflecting the more complicated decision-making process surrounding adjuvant chemotherapy, the consensus panel said chemotherapy should be the mainstay of treatment for patients with triple-negative breast cancer. For HER2-positive patients, clinical trial evidence for trastuzumab is limited to its use with or after chemotherapy. Less consensus exists about its use in patients with estrogen receptor (ER)-positive, HER2-negative disease.

The corollary to recommendations about endocrine and anti-HER2 therapy is that “ER and HER2 must be reliably and accurately measured.”

Any method of ER staining is acceptable. However, the panel recommended adherence to American Society of Clinical Oncology/College of American Pathologists guidelines for assessing HER2 status.

The consensus guidelines include summaries of the state of knowledge in disciplines relevant to early breast cancer, as presented and discussed at the consensus meeting.

Examples include chemoprevention with selective estrogen receptor modulators, the role of stem cells in breast cancer, implications of circulating tumor cells, angiogenesis, pharmacogenetics, novel imaging techniques, and novel systemic therapies.

Although focused on systemic therapy, the consensus panel expressed support for continued refinement of surgical and radiation techniques to ensure the best possible outcome with the least possible morbidity.

The panel was circumspect on use of genetic testing in making treatment decisions, reflecting the controversy surrounding the issue.

Panelists avoided the term “gene assay,” and said genetic testing might have some value if doubt remains after reviewing all other factors and a test is readily available.

“There was clearly a division of opinion, largely on geographic grounds,” panelist Alan Coates, MD, of the University of Sydney, Australia, said in an interview.

“Many of the U.S. representatives and some Europeans were keen to say these tests are now established sufficiently, and that they are not only useful for prognosis, but also helpful to decide whether it will be valuable at prediction of the additional benefit of chemotherapy.

“Others felt that because two of the principal trials investigating markers for exactly that purpose have yet to report any results, as such, it is premature to make that conclusion. I must say I tend toward the second point of view, but there was a clear division on the panel.”

The 43-member panel drafted the recommendations in March at the 11th St Gallen (Switzerland) consensus meeting, which had a total attendance of almost 5,000.

The published consensus did not include disclosures of potential conflicts of interest.

Primary source: Annals of Oncology

Source reference:

Goldhirsch A, et al “Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009″ Ann Oncol 2009; DOI:10.1093/annonc/mdp322.

Two new studies from The Children’s Hospital of Philadelphia advance the search for genetic events that result in neuroblastoma, a puzzling, often-deadly type of childhood cancer.

Originating in the peripheral nervous system, neuroblastoma is the most common solid cancer of early childhood and causes 15 percent of all childhood cancer deaths.

“Only two years ago we had very little idea of what causes neuroblastoma,” said study leader John M. Maris, M.D., chief of Oncology and director of the Cancer Center at The Children’s Hospital of Philadelphia. “Now we have unlocked a lot of the mystery of why neuroblastoma arises in some children and not in others.”

In the largest gene study to date in pediatric oncology, Maris’s study team performed a genome-wide association study to discover that common variants in the gene BARD1 increase a child’s susceptibility to a high-risk form of neuroblastoma.

A second genome-wide study found that a copy number variation (CNV) a missing stretch of DNA along a structurally weak location on chromosome 1 plays an important role in the development of neuroblastoma. Although CNVs have received much attention from genetics researchers over the last several years, this study was the first example of a specific CNV that predisposes people to cancer.

The BARD1 study was published online in Nature Genetics on May 3, while the CNV study appears in tomorrow’s issue of Nature. The researchers made use of highly automated gene-analyzing technology at the Center for Applied Genomics at Children’s Hospital, directed by Hakon Hakonarson, M.D., Ph.D., a co-author of both studies. They used specimens collected from around the world through the Children’s Oncology Group.

The BARD1 gene had already attracted attention from oncology researchers because it is associated with the gene BRCA1, which was the first discovered familial breast cancer gene. “Researchers have suspected that variants in BARD1 also increased the risk of breast cancer, but no one has found compelling evidence of this,” said Maris. “Instead, surprisingly, our genome-wide association studies found that BARD1 is a susceptibility gene for neuroblastoma, and perhaps other cancers as well.”

Maris added that researchers are now working to understand the mechanism by which BARD1 gene variants act on developing nervous system cells to give rise to cancer during fetal or early childhood development.

Maris’s second study, spearheaded by Dr. Sharon Diskin, also of The Children’s Hospital of Philadelphia, found that an inherited CNV located at chromosome 1q21.1 is associated with neuroblastoma. The chromosome region contains a large family of genes that are involved in the development of the nervous system, and the CNV they discovered changes how much of one particular gene is made within normal nerve and neuroblastoma cells.

This study, Maris added, opens up a new area for studying the mechanisms of how CNVs may increase the risk of cancer.

The current findings build on 2008 studies by Maris’s lab, one identifying the ALK gene as the major gene predisposing patients to the rare familial form of neuroblastoma, and the other identifying a region of chromosome 6 that increases the risk of the nonhereditary form of the disease. The ALK gene discovery has already led to a clinical trial led by Dr. Yael Mosse of The Children’s Hospital of Philadelphia.

As gene studies continue to better define the genetic landscape of neuroblastoma, added Maris, pediatric oncologists can better develop more precise targeted treatments to improve survival and quality of life for children with this complex disease. The Cancer Center at Children’s Hospital has one of the nation’s largest research and clinical programs in pediatric oncology.

DNA samples for both studies were provided by the Children’s Oncology Group, a multicenter collaborative research organization in which Maris chairs the committee overseeing basic and clinical research in neuroblastoma. A variety of funding sources supported both studies, including the National Institutes of Health, the Alex’s Lemonade Stand Foundation, the Evan Dunbar Foundation, the Rally Foundation, the Andrew’s Army Foundation, the Abramson Family Cancer Research Institute and the Giulio D’Angio Endowed Chair.

Maris is also on the faculty of the University of Pennsylvania School of Medicine. Scientists from six other centers in addition to Children’s Hospital and the University of Pennsylvania contributed to the discovery or replication of the findings.

Source: Children’s Hospital of Philadelphia