1. Goodwin, Peter M.

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AMSTERDAM, Netherlands-Hopes that a sub-group of patients with breast cancer could be treated with surgery plus anti-HER2 therapy alone-without cytotoxic chemotherapy-were raised at the European Breast Cancer Conference by Judith Bliss, MSc, Professor of Clinical Trials at The Institute of Cancer Research, London, from a trial of preoperative lapatinib plus trastuzumab in patients with operable newly diagnosed HER2+ primary breast cancer.

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Bliss reported "exquisite" biological responses with significant reduction or absence of invasive disease in approximately 25 percent patients after only 11 days of preoperative combination anti-HER2 therapy. "This does offer us potential in the future to identify a group of patients who could be particularly targeted for treatment around their response to anti-HER2 therapy," she told OT.


But she added it would be a retrograde step to withhold cytotoxic drugs at the moment. "Before we can start saying [that] this patient doesn't need chemotherapy, we really do need further trials to formally compare the avoidance of cytotoxic chemotherapy [with] the complete package [of treatments] which has really improved outcomes so much in recent years," she said.


Co-author Nigel Bundred, MD, FRCS, Professor of Surgical Oncology at the University of Manchester and University Hospital of South Manchester, said, "This has ground-breaking potential because it allows us to identify a group of patients who, within 11 days, have had their tumors disappear with anti-HER2 therapy alone and who potentially may not require subsequent chemotherapy."


Bundred said it offered the opportunity to tailor treatment for each individual woman because giving treatment while waiting for surgery might identify a group of patients whose disease is particularly sensitive to anti-HER2 therapy. "And this would allow individualization of therapy in women with HER2 positive cancers," he said.


Study Results

The Effect of Peri-Operative Anti-HER-2 Therapy on Overall Survival-Biological Phase (EPHOS B) study (Abstract 6LBA) was designed to exploit the "window" between diagnosis and surgery to assess biological drug effects in terms of proliferation and apoptosis in patients with HER2 positive treatment-naive primary breast cancer patients who received 10-12 days of preoperative anti-HER2 therapy.


The trial included 257 women with newly diagnosed, operable HER2 positive disease. Initially, patients were randomized to having no preoperative treatment (the control arm), trastuzumab only, or lapatinib only. But as evidence emerged on the safety and efficacy of combination anti-HER2 therapy, the protocol was amended to no preoperative treatment, trastuzumab only, or a combination of lapatinib and trastuzumab.


The study looked for changes of at least 30 percent in the Ki-67 marker of proliferation and also for progesterone receptor and activated caspase-3 as markers of apoptosis. Tissue samples were taken at diagnostic core biopsy and at surgery, while patients who did not have enough tumor at surgery to assay for markers were categorized as having pathological complete response (pCR), minimal residual disease if the tumor was less than 5mm in diameter (MRD), or "other."


Bliss reported that Ki-67 fell by at least the index 30 percent in more than a third of patients treated with trastuzumab alone, in just under two-thirds of those who took lapatinib alone and in about three-quarters of the patients on the combined anti-HER2 therapy.


Eleven percent of women who received the combination treatment had pCR and 17 percent had MRD. This was in contrast to the response rates for single agent anti-HER2 therapy. As in the control group, none of the women randomized to receive only lapatinib had either pCR or MRD. In the trastuzumab-only group, there weren't any complete remissions; however, one patient had MRD.


In a small group of patients-mainly those who received combination anti-HER2 therapy-no invasive tumor remained at the tumor site at the time of surgery on which to perform an analysis of Ki-67. "So we have a group of patients-about 10 percent-for whom there appears to be no evidence of invasive tumor left after 11 days treatment with the combination therapy and a further group-about 17 percent-for whom there was only minimum residual disease-less than 5 mm of invasive tumor," Bliss said.


Researchers Weigh In

When asked about the clinical implications, Bliss told OT she was cautious, emphasizing the need for further research to look for reductions in recurrence rates, long-term disease control, and improved overall survival.


To try to understand this group of patients better, she said studies were needed in which patients could have an initial biopsy followed by two weeks of combination anti-HER2 therapy, have a second biopsy to identify responders, and then randomize these patients to continue with standard of care or further targeted anti-HER2 therapy without cytotoxic chemotherapy.


Conference Chair Fatima Cardoso, MD, Director of the Breast Unit of the Champalimaud Clinical Centre in Lisbon, Portugal, said the results confirm previous initial suggestions that there might be patients who can be treated with dual blockade alone without chemotherapy.


Cardoso told OT the study was very interesting because a short period of treatment with two targeted agents led to disappearance of invasive breast cancer. "This has been seen before with other trials of longer treatment duration without chemotherapy. So altogether what this means is that [there's] certainly a subgroup of these patients who-most probably-can be treated without chemotherapy-just with a targeted agent."

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Cardoso said these patients need to be identified and included in a large study comparing chemotherapy with a targeted approach to confirm that in terms of survival and relapse this approach is as good as or better than chemotherapy.


Karen Gelmon, MD, Professor of Medicine at the University of British Columbia and Medical Oncologist at the BC Cancer Agency in Vancouver, said the new thing the study shows is that responses to dual anti-HER2 blockade can be found early. Although she did not regard lapatinib plus trastuzumab as the optimal combination, this research had nevertheless shed light on what could come. "I think these kinds of studies showing response early are helpful in terms of developing new agents," she said.


When she was asked about the impact of the results, she said it wasn't going to change the approach to patients. "I think it is a framework for clinical trials groups to do subsequent studies in new agents looking for early response," Gelmon said. "We might spare doing some of the larger trials for inadequate drugs or we might go ahead with more enthusiasm for drugs that show promise."


Peter M. Goodwin is a contributing writer.