The availability of effective therapies for HER2-positive tumors has made breast cancer a better managed disease, but outcomes could be further enhanced through the targeting of other players in this pathway, emerging data suggest.

C. Kent Osborne, MD, of Baylor College of Medicine, Houston, commented on the pivotal CLEOPATRA trial of dual HER2 blockade and described future approaches he believes will make treatment of HER2-positive patients even more effective.

As background, Dr. Osborne emphasized the need to move beyond trastuzumab (Herceptin) alone in HER2-positive disease. Trastuzumab works predominantly by inhibiting signaling from HER2 homodimers, and it induces antibody-dependent cell-mediated cytotoxicity (ADCC), but has no effect against HER1 homodimerization or HER1/HER3 heterodimerization, he pointed out.

“This raises the possibility that incomplete blockade of the HER receptor layer by trastuzumab is a common mechanism of resistance,” he said.

Fortunately, other drugs can fill this gap. Pertuzumab can inhibit heterodimerization of HER1/HER2 and of the most potent of the HER family members, HER2/HER3. Additional HER family signaling is inhibited variously by the epidermal growth factor receptor inhibitors and by dual or pan tyrosine kinase inhibitors. Trastuzumab must remain part of any regimen, however, for optimal activity. 

What If ER Is Also Targeted?

In CLEOPATRA, the combination of trastuzumab and pertuzumab led to “impressive” response rates, with “striking” improvements in progression-free and probably overall survival, Dr. Osborne noted. “For patients meeting the study’s eligibility criteria, this is clearly a new standard and should be practice-changing,” he told attendees.

But in this and other studies in HER2-positive patients, the effects were less dramatic among estrogen receptor (ER)-positive patients. That could be because ER-positive patients are less sensitive to chemotherapy, or because ER was not simultaneously targeted therapeutically, he suggested.

“Complete responses were rare, obviously because multiple survival pathways are functioning in metastatic HER2 tumors,” he said. He noted that in NeoALLTO (lapatinib [Tykerb]/trastuzumab) and NeoSphere (pertuzumab/trastuzumab), lower pathologic complete respones are seen in ER-positive patients (who were not treated with endocrine therapy).

“We would not think of not targeting HER2 if it is overexpressed. So when ER is positive, we need to target that as well,” Dr. Osborne maintained. In CLEOPATRA, 49% of patients were ER-positive but did not receive endocrine therapy.

“We actually know very little about combining estrogen deprivation with chemotherapy, and since the effects on the cell are so completely different, one could imagine that ER deprivation combined with chemotherapy might be better. This is something we need to study,” he said.

In addition, in CLEOPATRA only 46% had received prior chemotherapy and 10% prior trastuzumab. “So a large number were treatment-naive, which raises some question as to whether this combination is applicable to more heavily pretreated patients,” he suggested (though the investigators said the outcomes were similar regardless of pretreatment).

“Certainly,” Dr. Osborne acknowledged, “this is a very well done study with convincing data, and the results speak for themselves … though one has to imagine what the effect would be of simultaneously targeting HER2 and ER.”

Evidence for More Inhibition Being Better

Preclinical studies have suggested that the more inhibition—and more agents in the mix—the better the outcomes. Anti-HER2 monotherapy only partially and temporarily inhibits growth in xenograft models; multidrug combinations are superior, though resistance still emerges. But when pertuzumab, trastuzumab, and gefitinib (Iressa, which inhibits HER1) are joined by tamoxifen or estrogen deprivation similar to an aromatase inhibitor in patients, there is true and durable eradication of tumor, according to work performed in Dr. Osborne’s lab. Similar results were observed when lapatinib and trastuzumab were combined with tamoxifen or estrogen deprivation.

“If you don’t target ER, even this potent cocktail is ineffective,” he observed. “Estrogen deprivation plus the triple combination is the most potent we have ever studied. All these tumors regressed, and none has ever come back with this four-drug regimen, suggesting you must target both drivers in patients whose tumors are both ER- and HER2-positive.” ■

Disclosure: Dr. Osborne has served on advisory boards for AstraZeneca, Novartis, GlaxoSmithKline, Boehringer Ingelheim, Genentech, and Pfizer.