Adjuvant T-DM1 versus trastuzumab in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer: subgroup analyses from KATHERINE

Abstract

Background: In the KATHERINE study (NCT01772472), patients with residual invasive early breast cancer (EBC) after neoadjuvant chemotherapy (NACT) plus human epidermal growth factor receptor 2 (HER2)-targeted therapy had a 50% reduction in risk of recurrence or death with adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab. Here, we present additional exploratory safety and efficacy analyses. Patients and methods: KATHERINE enrolled HER2-positive EBC patients with residual invasive disease in the breast/ axilla at surgery after NACT containing a taxane (AE anthracycline, AE platinum) and trastuzumab (AE pertuzumab). Patients were randomized to adjuvant T-DM1 (n ¼ 743) or trastuzumab (n ¼ 743) for 14 cycles. The primary endpoint was invasive disease-free survival (IDFS). Results: The incidence of peripheral neuropathy (PN) was similar regardless of neoadjuvant taxane type. Irrespective of treatment arm, baseline PN was associated with longer PN duration (median, 105-109 days longer) and lower resolution rate (w65% versus w82%). Prior platinum therapy was associated with more grade 3-4 thrombocytopenia in the T-DM1 arm (13.5% versus 3.8%), but there was no grade !3 hemorrhage in these patients. Risk of recurrence or death was decreased with T-DM1 versus trastuzumab in patients who received anthracycline-based NACT [hazard ratio (HR) ¼ 0.51; 95% confidence interval (CI): 0.38-0.67], non-anthracycline-based NACT (HR ¼ 0.43; 95% CI: 0.22-0.82), presented with cT1, cN0 tumors (0 versus 6 IDFS events), or had particularly high-risk tumors (HRs ranged from 0.43 to 0.72). The central nervous system (CNS) was more often the site of first recurrence in the T-DM1 arm (5.9% versus 4.3%), but T-DM1 was not associated with a difference in overall risk of CNS recurrence. Conclusions: T-DM1 provides clinical benefit across patient subgroups, including small tumors and particularly high-risk tumors and does not increase the overall risk of CNS recurrence. NACT type had a minimal impact on safety.

Role of Post-Neoadjuvant therapy with trastuzumab emtansine in HER2-positive breast cancer

“…Если мы обратимся к характеристикам больных, включенных в исследование KATHERIN, то увидим, что подавляющее большинство пациенток имели люминальный Her2положительный подтип -72% [26,27], что также объясняется более низкой частотой pCR в этой когорте. Однако постнео-Target therapy of tumors адъювантная терапия трастузумабом эмтанзином показала свою эффективность относительно выживаемости без инвазивной опухоли вне зависимости от рецепторного статуса [23,28]. Результаты же недавно опубликованного продгруппового анализа исследования KATHERINE [23] демонстрируют самые высокие показатели 3-летней IDFS как раз в группе исходно резектабельного гормонрецептор положительного рака с поражением л/узлов -91,4%, в сравнении с 77,2% в контрольной группе, достоверное снижение риска прогрессирования для таких пациентов составило 57% (ОР 0,43, 95% ДИ 0,25-0,75) (табл.…”

“…При медиане наблюдения 30,5 мес. значительно большая медиана ОВ наблюдалась Важно отметить, что частота поражения центральной нервной системы (ЦНС) в качестве первого сайта метастазирования была выше в группе терапии T-DM1: 5,9% про-тив 4,3% в группе трастузумаба, тем не менее общее число больных с поражением ЦНС было сопоставимо в двух когортах: 6,1% и 5,4%, соответственно [23]. Поражение головного мозга как единственное проявление метастатической болезни чаще отмечалось в группе трастузумаба эмтанзина: 4,8% в сравнении с 2,8% в контрольной группе.…”

Perioperative HER2 targeted treatment in early stage HER2-positive breast cancer

“…Moreover, T-DM1 showed consistent efficacy regardless of type of neoadjuvant chemotherapy. 49 Based on these results, adjuvant T-DM1 is a standard of care in residual HER2-positive breast cancer patients after neoadjuvant treatment and surgery in the latest NCCN and ESMO guidelines as of 2021. 41 , 42…”

Role and evaluation of pathologic response in early breast cancer specimens after neoadjuvant therapy: consensus statement

“…Adjuvant therapy after NAT and surgery is justified, especially for HER-2-positive and triple-negative tumours, regardless of the size of the residual tumour, although the size does have an effect on the patient's prognosis. [19][20][21][22] Accurate sampling of the surgical specimen is therefore essential so as not to miss any residual tumour. For surgical resection following NAT, it is necessary to ink the margins, slice the specimen serially at 0.5 cm intervals, and sample the tumour bed, mapping the different sections with diagrams and photographs, to reconstruct the size of the residual tumour, if any, and of the tumour bed.…”