T-VEC virotherapy and NAC improves response in triple negative breast cancer

23rd February 2023

T-VEC (talimogene laherparepvec) virotherapy with neoadjuvant chemotherapy (NAC) improves the response rate in triple negative breast cancer

In a phase 2 trial of adding talimogene laherparepvec (T-VEC) to neoadjuvant chemotherapy (NAC) in patients with triple negative breast cancer, researchers from the Moffitt Cancer Center, Florida, observed an improved estimated pathological complete response rate.

Triple negative breast cancer accounts for 10 to 15% of all breast cancers and chemotherapy has become the established treatment for both early and advanced disease. In a phase 1 trial reported in 2021 among 9 women with stage II to III triple negative breast cancer, use of T-VEC in combination with neoadjuvant chemotherapy, led to a complete response rate of 55%. The rational for T-VEC is based on the notion that the oncolytic virus selectively replicates within tumour cells and produces granulocyte-macrophage colony-stimulating factor which enhances both the local and systemic anti-tumour response. In fact, T-VEC (brand name Imlygic) is already licensed for the treatment of adult patients with unresectable melanoma which has become both regionally and distantly metastatic but without bone, brain, lung or other visceral disease.

Following the success of the phase 1 trial, the US researchers continued to explore the utility of this therapeutic approach by undertaking a phase 2 trial of T-VEC in patients with stage II to III triple negative breast cancer, followed by doxorubicin and cyclophosphamide chemotherapy prior to surgery, to assess residual the cancer burden index. Eligible patients received a total of five doses of intra-tumoral T-VEC injection, given initially at week 1, followed by four subsequent doses on weeks 4, 6, 8 and 10 concurrently with intravenous once-weekly paclitaxel. The primary outcome of interest was a pathological complete response (RCB0), defined as no residual invasive disease in the breast or sampled nodes after completion of NAC. The secondary endpoint was the RCB0-1 rate.

T-VEC and pathological complete response

A total of 37 women with a median age of 49 years, the majority of whom (84%) had stage II disease were included in the study.

A total of 16 women had a pathological complete response with an estimated RCB0 response of 45.9%. In addition, 8 patients had RCB1 minimal residual disease, giving a descriptive RCB0-1 rate of 65%. The authors added that the 2-year disease-free event rate was equal to 89% with no recurrence in RCB0-1 patients.

The researchers concluded that the use of T-VEC when added to NAC may increase RCB0-1 rates and called for continued investigation of this strategic approach in women with triple negative breast cancer.

Citation
Soliman H et al. Oncolytic T-VEC virotherapy plus neoadjuvant chemotherapy in nonmetastatic triple-negative breast cancer: a phase 2 trial. Nat Med 2023

Adjuvant pembrolizumab increases event-free survival in triple negative breast cancer

18th February 2022

Adjuvant pembrolizumab in addition to chemotherapy has been found to improve event-free survival in triple negative breast cancer patients

Adjuvant pembrolizumab added to chemotherapy post surgery significantly improves event-free survival compared to chemotherapy alone. This was the conclusion of a study by researchers from the Centre of Experimental Cancer Medicine, Barts Cancer Institute, London, UK.

Triple negative breast cancer constitutes 10-15% of female breast cancers and is a more aggressive cancer with more frequent recurrence and worse survival compared with the non-triple negative form.

Clinical trial data has revealed improved disease-free survival with postoperative chemotherapy in patients with either triple-negative or HER2-positive breast cancer who had residual disease after neoadjuvant chemotherapy.

Whether the addition of pembrolizumab to neoadjuvant chemotherapy would increase the proportion of patients with early triple-negative breast cancer who had a pathological complete response after surgery was unclear until publication in 2020, of the KEYNOTE-522 trial.

The trial concluded that the percentage of patients with a pathological complete response was significantly higher among those who received pembrolizumab plus neoadjuvant chemotherapy than among those who received placebo plus neoadjuvant chemotherapy.

For the present study, the authors have reported on an updated analysis of the KEYNOTE-522 trial and in particular, event-free survival as well as additional efficacy and updated safety information. Participants were adults with confirmed triple negative breast cancer or those with newly diagnosed and previously untreated non-metastatic disease with primary tumour and regional lymph node involvement.

During the adjuvant phase, patients with previously untreated stage II or III triple negative breast cancer, were randomised 2:1 to receive either pembrolizumab (the pembrolizumab–chemotherapy group) or placebo (the placebo–chemotherapy group), administered once every 3 weeks.

After surgery, patients received either pembrolizumab or placebo and chemotherapy every 3 weeks for up to nine cycles. The primary endpoint was pathological complete response and event-free survival.

Adjuvant pembrolizumab and event-free survival

A total of 1174 patients were randomly assigned to either arm and during follow-up, 123 (15.7%) patients assigned to the pembrolizumab arm had an event or died compared to 93 (23.8%) in the placebo-chemotherapy arm.

The estimated event-free survival after 36 months was 84.5% in the adjuvant pembrolizumab group and 76.8% in the placebo arm, giving a hazard ratio, HR, for an event or death = 0.63, 95% CI 0.48 – 0.82, p < 0.001.

Data on overall survival were described as immature at the time of the analysis and the estimated overall survival at 36 months was 89.7% in the adjuvant pembrolizumab group and 86.9% in the placebo-chemotherapy group. With respect to safety, the authors reported that the reported adverse events were consistent with the established safety profile of both pembrolizumab and chemotherapy.

The authors concluded that among those with early triple negative breast cancer, neoadjuvant pembrolizumab plus chemotherapy and then followed by adjuvant pembrolizumab after surgery, was associated with a significantly longer event-free survival than neoadjuvant chemotherapy alone.

Citation
Schmid P et al. Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer N Engl J Med 2022

MRI radiomics model predicts disease recurrence in triple negative breast cancer after neoadjuvant chemotherapy

13th December 2021

An MRI radiomics model shows good predictive accuracy for the 3-year triple negative breast cancer recurrence after neoadjuvant chemotherapy

An MRI radiomics model based on deep learning has shown good predictive accuracy at identifying whether patients with triple negative breast cancer (TNBC) would have systemic recurrence within three years of neoadjuvant chemotherapy, according to researchers from the Department of Radiology, Peking University, Beijing, China.

A triple negative breast cancer describes an aggressive tumour which lacks expression of oestrogen receptor, progesterone receptor and HER2 and accounts for around 15% of all breast cancers. Moreover, TNBC has been found to have the lowest 4-year survival rate at 77%.

Neoadjuvant chemotherapy is seen as the mainstay of treatment for early stage TNBC followed by definitive surgery although relapse within 3 years has been found to occur in up to 97% of patients. Magnetic resonance imaging (MRI) has been used to enable prediction of disease recurrence although these MRI radiomics models have required a radiologist to manually draw regions of interest (ROIs) as the input which is very time-consuming.

In the present study, the Chinese team used radiomics based on deep learning models and which utilised automated segmented ROIs of breast tumours from MRI images to predict whether patients with TNBC who had received neoadjuvant chemotherapy, would experience disease recurrence within three years of treatment. The team undertook a retrospective analysis of consecutive female patients with unilateral primary TNBC and for whom pre- and post-neoadjuvant MRI imaging was available. The researchers also collected clinico-pathologic factors from the patient medical records, e.g., menopausal status, the histological type of cancer, the clinical T and N stages. They developed a MRI radiomics model based on three separate features; pre-treatment features (model 1), post-treatment features (model 2) and a combination of pre and post-treatment MRI features (model 3). Multivariate analysis was used to assess associations between clinical factors and disease recurrence and the predictive performance of the models was assessed using the receiver operating characteristic curves and the area under the curves (AUC).

Findings

A total of 147 women with a median age of 49.5 years were included in the analysis, 104 (22 with disease recurrence) were used for the training cohort and 43 for the testing cohort (9 with disease recurrence) and the median time to disease recurrence was 17 months.

In both the univariate and multivariate analysis the clinical T stage and pathological T stage were significantly associated with systemic disease recurrence within three years of treatment (p < 0.05). Using these two variables in a clinical model yielded AUCs of 0.75 for the training cohort and 0.74 in the testing cohort. In comparison, the AUCs for each of the MRI radiomics model was 0.88 (model 1), 0.91 (model 2) and 0.96 (model 3).

Model 3 had a perfect sensitivity (i.e., 1) and a specificity of 0.85 compared to a sensitivity of 0.67 and specificity of 0.82 for the clinical model and this difference was statistically significant (p < 0.05). However, neither model 1 or 2 were significantly better than the clinical model.

Commenting on their findings, the authors speculated that the predictive ability of the third MRI radiomics model was likely to have a greater prognostic value by inclusion of post-neoadjuvant chemotherapy features that were reflective of treatment-induced changes.

They concluded that the value of their non-invasive model was in being able to more easily identify those at risk of disease recurrence and to therefore strengthen the treatment of these patients after surgery to improve their prognosis.

Citation

Ma M et al. Radiomics features based on automatic segmented MRI images: Prognostic biomarkers for triple-negative breast cancer treated with neoadjuvant chemotherapy Eur J Radiol 2021