Immunotherapy Before Surgery May Be Beneficial in High-Risk Breast Cancer

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Breast cancer cells, SEM
Breast cancer cells. Coloured scanning electron micrograph (SEM) of breast cancer cells. The cells shows numerous processes and microplicae (fine surface folds). These features are characteristic of highly mobile cells, and enable cancerous cells to spread (metastasis) rapidly round the body, and invade other organs and tissues. Cancer cells divide rapidly and chaotically, and may clump to form malignant tumours. The tumours often invade and destroy surrounding tissues. Breast cancer is the most common form of cancer in women. Treatment involves surgical removal of the tumour, often combined with radiotherapy and chemotherapy. Magnification: x3500 when printed 10cm wide.

A change of protocol for treating breast cancer has yielded positive results for researchers at Yale Cancer Center (YCC). A new study shows women with high-risk HER2-negative breast cancer treated with immunotherapy and then surgery, and given a PARP inhibitor with chemotherapy, have improved treatment results.

“The results provide further evidence for the clinical value of immunotherapy in early stage breast cancer and suggest new avenues to use these drugs, particularly in estrogen receptor (ER)-positive/HER2-negative breast cancers,” said Lajos Pusztai, M.D., professor of Medicine at YCC. Pusztai presented the results of the study today during a plenary session at the American Association for Cancer Research (AACR) meeting.

Results from the test group have shown a higher rate of complete eradication of cancer from the breast and lymph nodes compared to chemotherapy alone. The findings were part of the I-SPY 2 clinical trial.

I-SPY (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis) 2 is a multi-center Phase II trial to evaluate novel agents as pre-surgical therapy for breast cancer. The study is a collaboration among 20 U.S. cancer research centers, the U.S. Food and Drug Administration and the Foundation for the National Institutes of Health Cancer Biomarkers Consortium.

I-SPY 2 is a long running clinical trial for breast cancer designed to test neoadjuvant treatment for locally advanced breast cancer. Physicians treated a control group of women with HER-2 negative breast cancer with chemotherapy before surgery, hoping to shrink the tumor and to guide treatment after the operation. For a subgroup of women, they were treated pre-surgery with chemotherapy, resulting in any evidence of the tumor being obliterated.  Clinically this is referred to as “pathologic complete response” (pCR), a condition that typically heralds increased overall survival.

Investigators in the I-SPY 2 clinical trial now report that for women with HER2-negative breast cancer who are treated before surgery, on average experience a 22% rise of pCR rate when treated with standard-of-care chemotherapy before surgery, and patients treated with the immunotherapy drug durvalumab, plus the PARP inhibitor drug olaparib, in addition to chemotherapy experienced a 37% rise.

Durvalumab is a checkpoint inhibitor immunotherapy that targets tumors with a PD-1 mutation. By targeting and inhibiting this protein, immune system T cells are able to attack target tumor cells and destroy them. PARP inhibitor drugs such as olaparib aim prevent cancer cells from repairing DNA damage caused by chemotherapy.

In the overall study, 73 patients in the experimental arm were treated with durvalumab, olaparib, and paclitaxel chemotherapy followed by doxorubicin/cyclophosphamide chemotherapy, while 229 patients in the control arm received the standard treatment of paclitaxel plus doxorubicin/ cyclophosphamide. Researchers analyzed the final results for all HER2-negative patients, as well as patients with triple-negative (TNBC) and ER positive breast cancer subsets.

They found that women with TNBC who received the combination treatment saw a pCR rate of 47%, compared to those given the standard chemotherapy, who had an average pCR rate of 27%. Patients with estrogen-positive/HER2-negative cancer in the experimental arm were reported to have a pCR rate of 28%, compared to 14% of those in the control arm. It is important to note that patients in the experimental arm were found to also be more likely to experience grade 3 serious adverse events—58% of patients in the experimental arm experienced such an event, compared to 41% of patients in the control arm.

Additional results from the study showed that tumors with a high level of immune cell infiltration reported higher pCR rates in all subtypes and in both treatment and control arms, but the investigators discovered this may be due to biomarkers that could identify which patients are most likely to benefit from combination durvalumab and olaparib treatment.

Among the estrogen-positive/HER2-negative cancers, the MammaPrint (a type of assay used to detect the likelihood of metastasis in breast cancer patients) ultra-high risk subset benefited the most from the drug combination, as seen from the average pCR group rate reaching 64%. In patients with TNBC, tumors with a low CD3/CD8 ratio, high Macrophage/Tcell-MHC class II ratio, and high proliferation rate appear to benefit preferentially when treatment included  adding durvalumab and olaparib to paclitaxel.

The results from this study indicate that earlier treatment with immunotherapy drugs is highly beneficial for breast cancer patients, particularly groups of patients most at risk for cancer recurrence.  It will be interesting to tract these results over time.

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