[Lani]

dfs=invasive disease free survival

from Med Page Today

Oncology/Hematology 01.07.2015

Less Toxic Breast Ca Regimen Deemed Successful

Study finds 98.7% rate of 3-year freedom from invasive recurrence or death.




by Charles Bankhead
Staff Writer, MedPage Today


Patients with small, node-negative, HER2-positive breast cancers had a 3-year survival approaching 100% with adjuvant paclitaxel and trastuzumab (Herceptin).

Note that safety results were generally good, as relatively few patients had grade 3 peripheral neuropathy, heart failure, or asymptomatic declines in left ventricular ejection fraction.

Patients with small, node-negative, HER2-positive breast cancers had a 3-year survival approaching 100% with adjuvant paclitaxel and trastuzumab (Herceptin), a multicenter, prospective trial showed.

The 406 patients included in the study had 3-year invasive disease-free survival (IDFS) of 98.7%. After excluding contralateral HER2-negative recurrences and nonbreast cancers, investigators identified seven disease-specific recurrences.


Safety results were generally good, as relatively few patients had grade 3 peripheral neuropathy, heart failure, or asymptomatic declines in left ventricular ejection fraction (LVEF), as reported online in the New England Journal of Medicine.

"The regimen we used in this study was associated with patient outcomes that were better than expected on the basis of historical data," Eric Winer, MD, of Dana-Farber Cancer Institute in Boston, and co-authors said in conclusion. "However, the study does not provide data to support the use of trastuzumab-based chemotherapy in all patients with small HER2-positive tumors, and there will be many patients with T1a disease and some with T1b disease who will decide with their physicians to avoid the toxic effects of a trastuzumab-based regimen."

The findings may help establish a standard of care for the subgroup of patients with small, node-negative, HER2-positive tumors, Winer said in a statement. Currently, no consensus exists about the most appropriate systemic therapy for the subgroup.

"This study demonstrates that a combination of lower-intensity chemotherapy and trastuzumab -- which is associated with fewer side effects than traditional chemotherapy regimens -- is an appealing standard of care for this group of patients," said Winer.

A chemotherapy-free regimen for such patients might even be possible for these patients, said Charles Shapiro, MD, of Dubin Breast Center at Mount Sinai Hospital in New York City.(my highlight...lani)


"The results beg the question: Is chemotherapy necessary? What about just trastuzumab alone in this stage I population?" Shapiro asked. "Two-thirds of the study population was also estrogen receptor-positive and also received antiestrogens, like tamoxifen, or aromatase inhibitors. Could this group of patients be treated with antiestrogens and trastuzumab?"

Winer and colleagues reported data from a trial designed to determine whether adjuvant paclitaxel-trastuzumab could achieve a low rate of recurrence with less toxicity as compared with conventional adjuvant chemotherapy regimens. Investigators in the nonrandomized, single-arm trial enrolled patients with HER2-positive, node-negative tumors <3 cm in size.

All patients received paclitaxel and trastuzumab, administered weekly for 12 weeks. At that point, patients could continue weekly trastuzumab or switch to a higher dose of trastuzumab administered every 3 weeks. Maintenance trastuzumab continued for 40 weeks.

Patients who underwent lumpectomy received either partial-breast or whole-breast irradiation, and patients with hormone receptor-positive tumors also received adjuvant endocrine therapy.

Investigators assessed LVEF function by echocardiography or MUGA scans at 12 weeks, 6 months, and 1 year. Trastuzumab was withdrawn if a patient developed grade 3 or 4 LVEF dysfunction, and dose interruptions came into play for patients who had prespecified declines in LVEF function.

The trial had a primary endpoint of freedom from invasive disease (recurrent or new invasive disease) and death from any cause. A 3-year event rate of 9.2% was defined in the trial protocol as unacceptable and an event rate ≤5% as successful. The data and safety monitoring board ended the trial after a third interim analysis that occurred after 1,316 patient-years of follow-up. The published results reflected 1,605 patient-years of follow-up.

Patients' median age was 55, and 272 (67%) had HR-positive tumors. Half of the patients had tumors ≤1 cm, and 9% had tumors that were 2 to 3 cm at the greatest dimension.

The authors reported that 356 (87.7%) of patients completed the planned 52 weeks of therapy. The median follow-up was 4.0 years and ranged to 6.2 years.

Twelve protocol-defined primary events were recorded: two patients with distant recurrence, four with local or regional recurrence, four contralateral breast cancer (three of which were HER2-negative), and two deaths (one resulting from rapidly progressing ovarian cancer and one resulting from a stroke). Additionally, four patients had new diagnoses of nonbreast cancer that was not considered relapsed/recurrent disease, as well as four patients who had new diagnoses of ductal carcinoma in situ, also not included in calculations of the primary endpoint.

The 3-year IDFS of 98.7% exceeded the 95% threshold prespecified as the definition of a successful trial (P<0.001).

During the 12 weeks of combination therapy, 14 (3.2%) patients had one or more episodes of grade 3 neuropathy; no grade 4 neurotoxicity was reported. Two patients (0.5%) had grade 3 systolic left ventricular dysfunction, and both recovered after discontinuation of trastuzumab. Additionally, 13 (3.2%) patients had clinically significant declines in LVEF necessitating interruption of trastuzumab treatment. Seven patients had grade 3/4 allergic reactions to study medication.

The study was supported by Genentech and by Susan G. Komen for the Cure.

Winer disclosed a relevant relationship with Genentech. One or more co-authors disclosed relevant relationships with Genentech, Roche, sanofi, Wyeth/Pfizer, Bristol-Myers Squibb, Novartis, GlaxoSmithKline, Medigene, AstraZeneca, and PAM50 Bioclassifier.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner
last updated 01.08.2015

Primary Source

New England Journal of Medicine

Source Reference: Tolaney SM, et al "Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer" N Engl J Med 2015; DOI: 10.1056/NEJMoa1406281.