Medical interview Liu Zhenzhen: Immunotherapy for early triple-negative breast cancer is gradually getting better

Breast cancer is a "female killer", and triple-negative breast cancer (TNBC) with ER (estrogen receptor), PR (progesterone receptor), and HER-2 negative is a type of breast cancer subtype with strong aggressiveness, high early recurrence rate and poor prognosis, accounting for about 15%~20%
of all breast cancers.
Triple-negative breast cancer is not sensitive
to commonly used treatments for breast cancer, such as endocrine therapy for hormone receptor high expression and targeted therapy for HER-2.
For triple-negative breast cancer, chemotherapy remains the treatment of choice
.
Today, when all cancers are embracing immunotherapy, "Physician News" specially invited Professor Liu Zhenzhen, director of the breast department of Henan Cancer Hospital, to bring the exploration and prospect
of immunotherapy for early triple-negative breast cancer.

01

Tumor characteristics are conducive to immunotherapy, and advanced TNBC exploration is dawning

From an immunological point of view, breast cancer is considered a "cold" tumor, however, studies have found that triple-negative breast cancer is characterized by high genetic instability and more complex
patterns of copy number change and structural rearrangement compared to other breast cancer subtypes.
Triple-negative breast cancer also has stronger immunogenicity, such as high tumor mutation burden, high proportion of tumor infiltrating lymphocytes, and high proportion of PD-L1 positive, suggesting that triple-negative breast cancer may benefit
from immunotherapy.

In patients with triple-negative breast cancer, inhibition of PD-1 and PD-L1 may be a useful therapeutic strategy
.
At that time, immune checkpoint inhibitors against PD-1/PD-L1 became a research hotspot in immunotherapy, bringing new ways for the treatment of malignant tumors and greatly improving the prognosis
of patients in lung cancer and melanoma.
Similarly, immunotherapy regimens based on PD-1 antibodies can improve the prognosis
of patients with advanced triple-negative breast cancer.
To summarize the results of relevant clinical studies, the response rate of immune checkpoint inhibitor monotherapy in advanced triple-negative breast cancer is not high
.
However, persistent responses from a subset of PD-L1-positive patients suggest that treatment with immune checkpoint blockade in combination with other treatment modalities may provide favorable results
.
Chemotherapy can potentially enhance immune response
after or during immune checkpoint inhibitor therapy by increasing the release of tumor cell antigens, inducing the expression of MHC-class I molecules, neoantigens, and PD-L1, and promoting dendritic cell activation.

Based on this principle, a combination regimen of anti-PD-1/PD-L1 monoclonal antibody and chemotherapy has been designed and applied, which has shown good results
in advanced triple-negative breast cancer.
With the release of the preliminary results of the IMpassion130 study, the significant efficacy of anti-PD-L1 monoclonal antibody atezolizumab combined with chemotherapy in advanced triple-negative breast cancer was confirmed, which opened the door to the clinical application of immunotherapy in breast cancer, and immunotherapy for triple-negative breast cancer is beginning to dawn
.
Subsequently, the publication of KEYNOTE-355 results confirmed the significant efficacy
of anti-PD-1 monoclonal antibody pembrolizumab in combination with chemotherapy in advanced triple-negative breast cancer.

02

TNBC neoadjuvant immunotherapy is beginning to emerge

While advanced breast cancer has achieved significant results, the research of immunotherapy in early triple-negative breast cancer is also
ongoing.
Neoadjuvant therapy is currently a standard treatment regimen for early-stage triple-negative breast cancer without high-risk factors, providing breast cancer patients with the opportunity
for down-stage surgery.
On the other hand, the prognosis can be judged by the efficacy of neoadjuvant therapy
.

Increased pCR rates translate into survival benefits
for patients after surgery.
Therefore, numerous clinical studies have made a variety of attempts on drug treatment regimens, hoping to improve the prognosis
of patients with triple-negative breast cancer by increasing the pCR rate.
Before immunotherapy entered neoadjuvant therapy, chemotherapy was the mainstay
of treatment.
Continuation of anthracyclines with purple shirt drugs can make the pCR rate of triple-negative breast cancer patients reach 34%, and the pCR rate can rise to 50% after platinum, but it has never become the new standard regimen
for neoadjuvant therapy of triple-negative breast cancer.
Patients who do not achieve pathologically complete remission (pCR) with neoadjuvant therapy may also benefit
from intensive treatment with capecitabine.

The publication of preliminary results of KEYNOTE-522 indicates a breakthrough in immunotherapy in neoadjuvant therapy for early triple-negative breast cancer, and the KEYNOTE-522 study is a phase III clinical trial to evaluate the efficacy and safety of
neoadjuvant pembrolizumab or placebo adjuvant therapy after neoadjuvant pembrolizumab plus chemotherapy and neoadjuvant chemotherapy alone, respectively, in patients with early triple-negative breast cancer 。 The study endpoints were designed with a double-endpoint design, i.
e.
, pathologic complete response at surgery (defined as pathologic stage ypT0 Tis ypN0, indicating no residual invasive carcinoma in the completely resected breast specimen and all sampled regional lymph nodes) and event-free survival
.
Compared with the placebo-chemotherapy group, the pCR rate in the pembrolizumab-chemotherapy group increased to 64.
8% (64.
8% vs 51.
2%, P=0.
00055); The fourth interim analysis showed a significant improvement
in event-free survival (EFS) in the pembrolizumab-chemotherapy group compared with the placebo-chemotherapy group.
The estimated EFS at 36 months was 84.
5% (95% CI: 81.
7~86.
9) in the pembrolizumab-chemotherapy group and 76.
8% (95% CI: 72.
2~80.
7)
in the placebo-chemotherapy group.
As the first prospective, randomized, placebo-controlled phase III trial of pembrolizumab in early triple-negative breast cancer in the neoadjuvant therapy stage, KEYNOTE-522 is of great significance, bringing neoadjuvant therapy for triple-negative breast cancer into the era of
immunotherapy.
Based on a series of excellent performances of KEYNOTE-522, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have approved pembrolizumab combined with chemotherapy for neoadjuvant therapy and subsequent adjuvant therapy
for high-risk early triple-negative breast cancer.
Recently, the State Food and Drug Administration also approved pembrolizumab in combination with chemotherapy for neoadjuvant therapy
in patients with early-stage high-risk triple-negative breast cancer (TNBC) who express PD-L1 (comprehensive positive score (CPS) ≥20) with well-validated tests.

The results of IMpassion031 reaffirm the advantages
of immunotherapy in neoadjuvant therapy in patients with triple-negative breast cancer.
The study is a multicenter, randomized, double-blind phase III clinical study with a total of 333 patients randomized 1:1 to receive atezolizumab plus chemotherapy (albumin paclitaxel sequential doxorubicin + cyclophosphamide) or placebo plus chemotherapy
.
Primary endpoints included pCR rates in intention-to-treat (ITT) and PD-L1-positive populations, and secondary endpoints included EFS, disease-free survival (DFS), OS, and drug safety
.
The median follow-up time of the trial group and the placebo group was 20.
6 months and 19.
8 months, respectively, and the pCR rate in the experimental group increased by 17% (58% vs.
41%, P=0.
0044) in the ITT population, while the pCR rate in PD-L1-positive patients increased by 19.
5% (68.
8% vs.
49.
3%, P=0.
021).

Subgroup analysis showed that even PD-L1-negative patients still had a trend of benefit in pCR (47.
7% vs.
34.
4%)
.
NCCN guidelines also update treatment options for triple-negative breast cancer, adding pembrolizumab in addition to paclitaxel plus carboplatin-sequential doxorubicin plus cyclophosphamide in patients with high-risk early-stage triple-negative breast cancer
.
Neoadjuvant therapy for early-stage triple-negative breast cancer may fully enter the era of
immunotherapy.

Although immunotherapy continues to make breakthroughs in triple-negative breast cancer, the current exploration of immunotherapy in the field of breast cancer is only the tip of the iceberg, and a series of challenges need to be overcome, such as the screening of immunotherapy beneficiaries, the selection of immunotherapy combination regimens, the timing of immunotherapy initiation, and the cycle of immunotherapy use
.
The continuous advancement of more research is expected to provide more options and supporting evidence for immunotherapy for triple-negative breast cancer, and continue to broaden the scope of application of immunotherapy in triple-negative breast cancer and even the entire field of breast cancer, benefiting the majority of patients
.

03

Professor Liu Zhenzhen concluded

Triple-negative breast cancer has a high degree of malignancy and poor prognosis, and its high degree of heterogeneity makes its treatment particularly difficult
.
How to achieve cure at an early stage is the goal
of clinicians and researchers.
A series of clinical studies have confirmed that the immunotherapy of triple-negative breast cancer has gradually entered the best situation, and through the full-chain closed loop of "clinical problems-basic research-clinical transformation", the territory of immunotherapy has been continuously improved and expanded, hoping to truly rewrite the treatment
of early breast cancer.

Expert profiles

Professor Liu Zhenzhen

Henan Provincial Cancer Hospital

Chief Physician of the Department of Breast of Henan Cancer Hospital

Director of Henan Breast Cancer Diagnosis and Treatment Center

Member of the Breast Cancer Professional Committee of the National Cancer Quality Control Center

Chairman of the Breast Cancer Expert Committee of Henan Cancer Diagnosis and Treatment Quality Control Center

Member of the Standing Committee of the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association

Member of Breast Cancer Group, Oncology Branch of Chinese Medical Association

Member of Breast Surgery Group, Surgical Branch of Chinese Medical Association

Member of the Standing Committee of the Breast Cancer Expert Committee of the Chinese Society of Clinical Oncology

Chairman-elect of Breast Disease Branch of Henan Medical Association

The author of this article: Liu Zhenzhen, Jiao Dechuang, Yue Xiayu

Typesetting: Hu Haiyan

Editor: Wang Lina

Review: Qin Miao

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