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.