HER2-Enriched Subtype Linked To Neoadjuvant Dual HER2 Blockade pCR

Tumour molecular subtype may influence the likelihood of a pathological complete response to combined lapatinib and trastuzumab given before surgery

medwireNews: PAMELA results indicate that human epidermal growth factor receptor 2 (HER2)-positive patients with early breast cancer are most likely to achieve a pathological complete response (pCR) to neoadjuvant lapatinib plus trastuzumab if their tumour has the HER2-enriched molecular subtype.

Patients with the HER2-enriched intrinsic molecular subtype were 6.2 times more likely to achieve pCR by time of surgery than those with other subtypes, say Aleix Prat, from the Hospital Clinic of Barcelona in Spain, and co-investigators.

“The evidence suggests that a subgroup of patients with early-stage HER2-positive breast cancer, mostly those with the HER2-enriched subtype, might not need chemotherapy if treated with dual HER2 blockade (and endocrine therapy if necessary)”, they comment in The Lancet Oncology.

The open-label phase II trial was conducted in patients with treatment-naïve, HER2-positive stage I–IIIA invasive breast cancer and any hormone receptor status, the authors explain in The Lancet Oncology.

The 151 participants were given an 18-week course of lapatinib 1000 mg/day plus a 8 mg/kg loading dose of trastuzumab, followed by 3-weekly doses of 6 mg/kg. Menopausal patients who were hormone receptor (HR)-positive were also given letrozole, whereas premenopausal women were given tamoxifen. Surgery was performed 1–3 weeks after the last dose.

In all, 30% of the patients achieved a pCR by time of surgery, but this was significantly more common in the 101 patients with the HER2-enriched subtype at day 0 of treatment than the 50 patients with other subtypes, at 41% versus 10%.

The absolute difference of 31% was higher than the preplanned threshold for significance of 27%, the researchers note.

A pCR was recorded in none of the 22 patients with the luminal A subtype, two of 16 patients with luminal B, one of the nine patients with basal-like subtype and two of the three patients with the normal-like molecular subtype.

Molecular subtype was successfully re-assessed on day 14 in 144 of the patients and at this time 68% of patients had switched subtypes, with 49% of patients classified as having normal-like tumours, 25% luminal A, 18% HER2-enriched, 6% basal-like and 3% luminal B.

At time of surgery, pCR was reported in 49% of those with the normal-like molecular subtype tumours on day 14 and 14% of those with other subtypes.

But of the 96 patients with HER2-enriched tumours at baseline, 75% had non-HER2-enriched tumours on day 14, with 72% of these switching to the normal-like subtype, 56% of whom had a pCR at baseline. This prompted the authors to suggest: “The switch to the normal-like subtype at day 14 was likely to indicate early tumour response and an increased proportion of normal breast tissue.”

When pCR was assessed by intrinsic tumour subtype and HR status, the researchers found that 32% of the 38 HR-positive patients with a HER2-enriched subtype achieved pCR, compared with 5% of those with other subtypes. And for HR-negative patients the corresponding rates of pCR were 46% and 27%.

Discussing their results for lapatinib plus trastuzumab further, the investigators conclude: “Although this treatment strategy is not ready for clinical implementation, our results open the door to further studies assessing long-term survival outcomes of dual HER2 blockade without chemotherapy in specific groups of patients selected on the basis of variables such as intrinsic molecular subtyping, early tumour response, and pathological response at surgery.”


Llomabart-Cussac A, Cortés J, Paré L, et al. HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer (PAMELA): an open-label, single-group, multicentre, phase 2 trial. Lancet Oncol; Advance online publication 23 February 2017. DOI: http://dx.doi.org/10.1016/ S1470-2045(17)30021-9  

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