Professor Yin Yongmei: Analysis of the mystery of breast cancer genes in the era of precision treatment

The 16th Shanghai International Breast Cancer Forum, co-sponsored by the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association, the Affiliated Tumor Hospital of Fudan University, and the Shanghai Anti-Cancer Association, will be held in Shanghai from October 21 to 23, 2021
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At this meeting, Professor Yin Yongmei from Jiangsu Provincial People's Hospital introduced the progress of breast cancer gene precision therapy, the key contents are as follows
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Expert Profile Professor Yin Yongmei Chief Physician, Professor, PhD Supervisor, Deputy Dean of the Women's and Children's Branch of Jiangsu Provincial People's Hospital, Vice President, Chinese Society of Clinical Oncology (CSCO), Vice President, Beijing Hesco Foundation, Vice President, CSCO Breast Cancer Expert Committee, Vice Chairman, China Anti-Cancer The Development History of the Association’s Breast Cancer Professional Committee Standing Committee CSCO Patient Education Expert Committee Designated Chairman Breast cancer is a highly heterogeneous type of tumor, and the study of its biological behavior and internal mechanism is helpful to the precise treatment of breast cancer
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Advances in basic research and technology promote the precise classification of breast cancer treatment
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Molecular classification has promoted the precise treatment of breast cancer, but there is still a huge unmet need for the refined management of subtype populations
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For example, for early stage operable breast cancer, the proportion of HR-positive and HER2-negative subtypes is very high, accounting for more than 60% of all breast cancer cases.
There is objectively a large room for further stratification in the prognosis and treatment needs.
, By no means one or two subtype classifications can meet the needs of individualized treatment
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Breast cancer gene expression profiling analysis provides more prognostic information and treatment targets for the management of various subtypes of breast cancer based on the original molecular typing
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Current status and strategies The driving genes of breast cancer are different at different stages of development.
1 Early breast cancer: Gene precision therapy, optimizing patient treatment strategies.
The OlympiAD study is the first phase III clinical study for precise breast cancer treatment under the guidance of genetic testing.
Prove the efficacy of gBRCA1/2 germline mutation/HER2-negative advanced breast cancer patients, the PARP inhibitor olaparib is better than chemotherapy, the objective response rate (ORR) reaches 60%, and the median progression-free survival (PFS) is extended to 7 months, reduce the risk of disease progression or death by 42%
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Olapali became the first breast cancer precision treatment drug based on gene mutation
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Towards an early population Based on the excellent data of the OlympiAD study, we have reason to believe that olaparib may also perform well in the treatment of early breast cancer, thereby further expanding the patient population
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The OlympiA study is the first phase III clinical study of PARP inhibitors for the adjuvant treatment of early breast cancer.
It aims to evaluate olaparib versus placebo in the early stage breasts with high clinicopathological risk, HER2-negative, and BRCA1/2 germline mutations.
The effectiveness and safety of adjuvant therapy for cancer, this research is also of milestone significance for the precise treatment of breast cancer
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An analysis performed after a median follow-up of 2.
5 years showed that the olaparib treatment group significantly improved 3-year invasive disease-free survival (iDFS) and distant metastasis-free survival (DMFS) compared with the placebo group
.

Olapali treatment reduced the risk of recurrence or death of invasive tumors by 42% (HR 0.
58; 99.
5% CI 0.
41 to 0.
82; P<0.
001)
.

The relative risk of remote recurrence or death was reduced by 43% (HR 0.
57; 99.
5%CI 0.
39 to 0.
83; P<0.
001)
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Although the overall survival (OS) benefit did not reach the pre-determined statistically significant level of difference (interim analysis requires P<0.
01), the trend of OS benefit is obvious, and it may become more significant with the extension of follow-up time
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The GeparOLA study explored the efficacy of paclitaxel combined with olaparib versus paclitaxel combined with platinum in the neoadjuvant treatment of early breast cancer, and further expanded the population to include BRCA1/2 mutations and homologous recombination repair defects (HRD) high-scoring breast cancers Patient
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The results showed that compared with paclitaxel combined with platinum, paclitaxel combined with olaparib can bring a higher pathological complete remission (pCR) rate (55.
1% vs 48.
6%) for neoadjuvant therapy
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Subgroup analysis showed that the olaparib group achieved a better pCR rate in the younger patient subgroup than the control group (76.
2% vs 45.
5%); in the HR+ subgroup, it also achieved a higher pCR rate than the control group ( 52.
6% vs 20.
0%)
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GeparOLA's research has pioneered the use of PARP inhibitors in neoadjuvant therapy, thereby moving the application of PARP inhibitors in breast cancer from the late stage to the early stage of neoadjuvant and adjuvant therapy.
At the same time, it is also steadily advancing from a single drug to a combination drug regimen.

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The NEOTALA study explored the effectiveness and safety of the PARP inhibitor Talazoparib as a single agent for neoadjuvant treatment of gBRCA1/2 mutation/HER2-locally advanced breast cancer
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The results showed that the pCR rate of Talazoparib monotherapy in the neoadjuvant treatment of gBRCA-mutated HER2-breast cancer reached 45.
8% (evaluable population) and 49.
2% (ITT population).
The pCR rate is comparable
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And Talazoparib was well tolerated, and no adverse reactions outside the safety spectrum occurred
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As a single-arm Phase II study, the NEOTALA study has shown amazing single-drug effects, but its conclusions still need to be confirmed by the Phase III study
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At the same time, the improvement of pCR requires prognostic testing
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Amplification of the mutant population A phase II basket trial in Belgium enrolled 72 patients with advanced cancer with somatic or germline mutations (ATM, CHEK2, NBN, BRIP1, MRE11A, RAD50, NBS1, RAD51C, etc.
) in the HR gene, using Simon The two-stage design principle evaluates the efficacy and safety of olaparib in such patients
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The results showed that olaparib showed activity in HR gene mutation breast cancer (PALB2, RAD51D) and was well tolerated
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The TBCRC048 study explored the efficacy of olaparib monotherapy in MBC patients with different gene mutations in the DDR pathway
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The study was divided into two cohorts.
Cohort 1 was patients with germline mutations in non-BRCA1/2 DDR-related genes, and cohort 2 was patients with BRCA1/2 mutations and DDR-related gene system mutations.
Both received olaparib monotherapy until progressed.
Or intolerance
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The results showed that the ORR of cohort 1 was 29.
6% and cohort 2 was 38.
5%.
The ORR of patients with BRCA1/2 mutation was significantly higher; Olapali could significantly improve the ORR of patients with BRCA1/2 mutation
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This result suggests that not only germline mutations of BRCA1/2 genes can predict efficacy, but DDR mutations also have a certain impact on efficacy.
Therefore, the application population of PARP inhibitors may be expanded, and further expansion of PARP inhibitor application population may lead to more Patients benefit
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The newly added therapeutic drug PARP inhibitor has shown excellent clinical efficacy in patients with homologous recombination-deficient cancer.
However, whether it is used as a single agent or a combination therapy, hematological toxicity and other toxicities limit the application of this type of drug
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This part of the adverse reactions may be derived from the inhibition of PARP2 by PARP inhibitors that are already on the market, and PARP2 is not necessary for curative effect
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Therefore, the new generation of selective inhibitor AZD5305 aims to overcome the side effects of existing PARP inhibitors and construct the next generation of PARP inhibitors
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The molecular mechanism of new potential therapeutic targets for breast cancer is very complex.
Therefore, in the post-PARP inhibitor era, there is a great clinical need to find therapeutic targets and analyze prognostic factors to benefit patients, which is helpful for drug development and new indications.
The expansion of breast cancer provides the possibility for individualized treatment of breast cancer
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2 Advanced breast cancer: genetic testing explores new targets and prolongs the survival of patients.
Compared with early breast cancer, advanced breast cancer is more heterogeneous and has more genomic mutation events
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HR-positive breast cancer In primary HR-positive breast cancer, the ESR1 gene mutation rate is less than 5%, but in advanced breast cancer patients who have previously received AI treatment, the ESR1 mutation frequency has increased significantly to 14%-54%
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Studies have found that ESR1 mutations are involved in endocrine resistance, and the treatment of patients with metastatic breast cancer whose driver gene ESR1 has been clearly mutated is being explored
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CDK4/6 inhibitors have brought higher clinical benefits to patients with advanced HR+, but the primary or secondary resistance to these drugs poses new challenges for endocrine therapy
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Target distribution after CDK4/6 inhibitor resistance, about 40% of HR+/HER2- advanced breast cancers have PIK3CA mutations, leading to endocrine resistance and treatment progress
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The results of the SOLAR-1 study showed that the PIK3CA mutant HR+/HER2-advanced breast cancer that progressed after AI treatment, the PI3K inhibitor Alpelisib combined with fulvestrant was significantly longer than the median PFS of fulvestrant alone (11 months) vs 5.
7 months, HR=0.
65, P<0.
001)
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In the SOLAR-1 study, 20 patients in the PIK3CA mutation cohort received CDK4/6 inhibitor treatment.
The median PFS in the Alpelisib combination group was 5.
5 months, and the control group was only 1.
8 months
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The BYLieve study showed that after PIK3CA mutation HR+/HER2-advanced breast cancer CDK4/6 inhibitor combined with AI treatment progressed, Alpelisib combined with fulvestrant achieved good clinical efficacy, and the 6-month disease-free survival rate was 50.
4%.
The study reached the primary endpoint
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The median PFS was 7.
3 months, the ORR was 17.
4%, and the clinical benefit rate was 45.
5%
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The mechanism of CDK4/6 inhibitor resistance is replicated, and the specific mechanism has not yet been elucidated
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The detection of gene expression profiles before and after the use of CDK4/6 inhibitors found that multiple genes were up-regulated or amplified.
Combination therapy for multiple targets may be a potential strategy to reverse the resistance of CDK4/6 inhibitors
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Triple-negative breast cancer based on the KEYNOTE-355 study, FDA approved pembrolizumab for the treatment of advanced triple-negative breast cancer with CPS≥10
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Based on the OlympiAD and EMBRACA studies, the FDA approved PARP inhibitors olaparib and Talazoparib for the treatment of people with gBRCA mutations
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Based on the ASCENT study, the FDA approved the antibody conjugate drug sacituzumab govitecan-hziy targeting TROP-2 antigen for the treatment of advanced triple-negative breast cancer
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Professor Shao Zhimin’s team from the Cancer Hospital of Fudan University proposed the “Fudan Classification” for the first time in the world, and accordingly divided triple-negative breast cancer into 4 different subtypes, providing a precise diagnosis and treatment plan for the effective treatment of triple-negative breast cancer
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The FUTURE-C-PLUS study showed that carrelizumab + anti-angiogenesis targeted drug famitinib + albumin paclitaxel first-line treatment of IM type advanced triple-negative breast cancer ORR is as high as 81.
3%, which is currently metastatic triple-negative The highest ORR achieved in the first-line treatment of breast cancer
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HER2 overexpression and HER2 mutation HER2 positive breast cancer development process HER2 mutation is associated with poor prognosis of breast cancer.
A study conducted by the Tumor Hospital of the Chinese Academy of Medical Sciences found that patients with HER2 positive and HER2 mutations had poor efficacy in first-line trastuzumab.
Good; patients with HER2 non-amplification and HER2 mutation, the effective rate of pyrrotinib can reach 40%
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Problems and challenges 1.
Early HR+ risk models such as Oncotype DX still need to be verified by the Chinese population
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2.
The treatment decision based on the tumor gene mutation profile still needs research and verification
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3.
The exploration of precision treatment of breast cancer from the perspective of genes is increasing day by day
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