Prof. Yingying Xu: From population selection to plan formulation, "re-understanding" of neoadjuvant treatment for breast cancer | 2021 CSCO BC

*Only for medical professionals to read for reference about neoadjuvant treatment of breast cancer, what new knowledge do you have? On April 9-10, 2021, the National Breast Cancer Conference and the Chinese Society of Clinical Oncology (CSCO) Breast Cancer Annual Meeting were officially held in Beijing, which is waning in spring.

CSCO Breast Cancer Annual Conference is one of the most influential academic events in the field of breast cancer in China.

The conference invited well-known experts and scholars at home and abroad to give speeches and discussions, and build a broad academic exchange platform for doctors and scholars.

Professor Xu Yingying from the First Affiliated Hospital of China Medical University shared the progress of neoadjuvant treatment of breast cancer at the 17th St.
Gallen International Breast Cancer Conference that had just ended, and delivered international voices to domestic scholars.

 St Gallen International Breast Cancer Conference (St Gallen for short) was founded in 1978 and is the world's most influential international conference on early breast cancer.
It is held every two years.

The meeting focused on reaching a consensus on clinical diagnosis and treatment, and finally voted on hot issues related to breast cancer treatment to reach the "St.
Gallen Consensus.
"
This consensus has important reference value for the diagnosis and treatment of breast cancer worldwide.

Based on the relevant content of the St Gallen conference and her own understanding, Professor Yingying Xu shared her new understanding of neoadjuvant therapy for breast cancer.

 Figure 1 The significance of neoadjuvant therapy "Re-understanding" Professor Xu Yingying said that after this year's St Gallen meeting, she had a new understanding of neoadjuvant therapy for breast cancer.

The first is the upgrading of the significance of neoadjuvant treatment: in terms of local treatment, in addition to down-stage surgery and breast-conserving, patients with good curative effects can also down-stage to protect the axilla; through neo-adjuvant treatment, not only drug sensitivity information can be obtained, but also in new treatments.
In the auxiliary process, the treatment strategy is adjusted according to the curative effect, and the auxiliary treatment is decided according to the curative effect after the operation.
At the same time, the neoadjuvant can create time for genetic susceptibility gene detection and is also a platform for new drug development.Figure 2 "Re-understanding" the implementation of neoadjuvant therapy: how to choose the three stages? The first stage: select the applicable population of neoadjuvant therapy The first stage of the implementation of the neoadjuvant process is patient selection.
Should all patients who need adjuvant chemotherapy receive neoadjuvant chemotherapy? 60% of the experts in the St Gallen meeting expressed opposition, because of concerns about overtreatment (such as low-risk HER2+ patients).

The 2021 American Society of Clinical Oncology (ASCO) guidelines update recommends neoadjuvant therapy for HER2-positive breast cancer with T1c and above.
The enrolled population of multiple neoadjuvant clinical trials includes T1c patients, and the operability in clinical practice is not strong .

The cT>2cm and cN>1 recommended by the National Comprehensive Cancer Network (NCCN) and CSCO guidelines are more reasonable as neoadjuvant indications for HER2+ breast cancer.

"Starting from actual clinical needs and oriented toward the purpose of treatment" is an important principle for selecting neoadjuvant populations in clinical practice.

Stage 2: Determine the standard plan for neoadjuvant treatment.
Although the national agency proposed pathological complete remission (pCR) as a surrogate endpoint for early breast cancer drug approval more than 10 years ago, 83.
05% of experts believe that the standard neoadjuvant treatment plan is determined It should be based on the event-free survival (EFS) or overall survival (OS) endpoint, and approval is not the same as the standard.

Adjuvant programs with evidence of survival are the standard programs for neoadjuvant therapy, and programs that can both increase pCR and improve survival on this basis are better programs.

In addition, some programs that can increase pCR without compromising survival are also optional programs starting from the purpose of local treatment (such as lowering the axilla).

 Figure 3 ■ Expansion of neoadjuvant for triple-negative breast cancer: platinum? Immune checkpoint inhibitors? 1.
The "anthracycline and yew" program is based on the addition of "platinum" triple-negative breast cancer lacking driver genes.
At present, it is based on the anthracycline and yew program.

On this basis, adding "platinum" as a routine neoadjuvant chemotherapy regimen, 60% of experts opposed it.

Summarizing previous studies, the platinum regimen only improves pCR, but does not improve disease-free survival (DFS), so it should not be a standard new supplement.

For young, BRCA-mutated triple-negative breast cancer, my country's guidelines and expert consensus propose optional platinum-containing programs (such as EC-TP).

 2.
Immune checkpoint inhibitors Because the results of KEYNOTE-522, IMpassion031, NeoTRIPaPDL1 three immune neoadjuvant tests are inconsistent, and PD-L1 is not proven to be an effective Biomarker, 90.
38% of experts oppose combining immunization on the basis of standard neoadjuvant chemotherapy Checkpoint inhibitors, 81.
13% of experts believe that PD-1/PD-L1 testing will not affect the recommendation of neoadjuvant immune checkpoint inhibitors.

In the future, we should further explore the dominant populations and compatibility programs of immune neoadjuvant therapy, and whether the value of the combination of cytotoxic drugs and immunity is to induce or kill.

Figure 4 ■ Optimization of neoadjuvant for HER2-positive breast cancer: selection of anthracyclines At this St Gallen conference, regarding the neoadjuvant treatment of HER2+ breast cancer, most experts believe that patients with positive lymph nodes should contain anthracyclines, while those with negative lymph nodes The patient may not contain anthracyclines.

Professor Yingying Xu pointed out that this embodies the concept of HER2+ breast cancer treatment optimization on the neoadjuvant platform.

For low-risk/sensitive patients, chemotherapy can be used to downgrade, such as THP and HP regimens; while high-risk patients are the most controversial, focusing on AC-THP and TCbHP regimens.

Although the pCR of TCbHP and the anthracycline-containing regimen in the Train-2 study was similar to the 3-year invasive disease-free survival (iDFS) rate, the current study of neoadjuvant and adjuvant therapy based on the dual target of Toto was summarized.
The data sample size is small and the survival follow-up time is short.
In the KATHERINE study of the new auxiliary-assisted enhancement model, the use of anthracycline is as high as 77.
9%.

Therefore, there is still no consensus to completely abandon the anthracycline.

 ■ Screening for neoadjuvant ER+/HER2- breast cancer: genetic testing defines endocrine-dominant populations.
Endocrine therapy is widely recognized as the main treatment for ER+/HER2- breast cancer.
However, neoadjuvant endocrine therapy has never become a routine, mainly because of the population There is a lack of standards in terms of, programs, treatment courses, and efficacy evaluations. Several large-scale prospective studies have confirmed that polygenic testing (21 genes, 70 genes) can assist in the decision-making of adjuvant chemotherapy exemptions, and some neoadjuvant studies have also shown that polygenic testing has a higher endocrine response rate and breast-conserving rate in patients with low risk.

In this meeting, 73.
58% of the experts supported the choice of polygenic testing for neoadjuvant endocrine therapy or chemotherapy for ER+/HER2- patients; 98.
21% of the experts believed that chemotherapy is not better for postmenopausal women with low-risk genomic characteristics of ER+/HER2- Endocrine therapy.

The predictors and prognostic indicators of neoadjuvant endocrine efficacy are also the focus of attention.
In the IMPACT and POETIC studies, the expression of Ki-67 at 2 weeks is related to the prognosis.

The ADAPT HR+/HER2- study organically combined 21 gene detection with Ki-67 changes.
After 2-4 weeks of neoadjuvant endocrine therapy, patients with RS 12-25 and Ki-67<10% were given endocrine therapy only for 5 years.
The iDFS rate can reach 92.
6%.

 Figure 5 Stage 3: Adjuvant treatment options after neoadjuvant ER+/HER2- breast cancer.
For patients with high residual tumor burden after neoadjuvant endocrine therapy, such as positive lymph nodes ≥ 4 or tumors> 5 cm, most experts support it.
Adjuvant chemotherapy.

In clinical practice in my country, neoadjuvant endocrine therapy is mostly used in postmenopausal patients who are contraindicated with chemotherapy for hormone receptors with strong positive hormone receptors, so they rarely switch to adjuvant chemotherapy after surgery.

For these patients, the follow-up endocrine treatment plan is also an urgent problem to be solved.

 ■ HER2+ breast cancer St Gallen experts believe that the initial lymph node status is related to the choice of adjuvant drugs.
In the case of neoadjuvant HP (trastuzumab+pertuzumab)+chemotherapy reaching pCR, support patients with initial lymph node positive to continue adjuvant dual targets For treatment, patients with negative lymph nodes were switched to single-target (trastuzumab) therapy.

However, Chinese experts believe that the original targeted therapy plan should be continued for postoperative adjuvant pCR patients.

In addition, based on the results of the KATHERINE study, St Gallen experts support all HER2+ tumors with residual lesions after standard neoadjuvant treatment, even patients with residual invasive tumors less than 5 mm should receive adjuvant T-DM1 treatment.

In consideration of national conditions, side effects and other factors, Chinese experts prefer to recommend HP plans for patients with near-pCR.

 ■ Triple-negative breast cancer is based on the results of the CREATE-X study, 87.
72% of experts support capecitabine as an intensive adjuvant treatment plan for residual lesions after neoadjuvant therapy.

Professor Xu Yingying pointed out that triple-negative breast cancer is highly heterogeneous, and future enhancement programs are not limited to capecitabine.
There are already some studies in progress, such as carboplatin, immune checkpoint inhibitors, and PARP inhibitors.

 Figure 6 summarizes Professor Xu's final conclusion: Although the current framework of neoadjuvant therapy is gradually improving, it is not perfect.

The selection of suitable populations should be more precise, such as the application of triple-negative breast cancer Fudan typing, PAM50 and other genetic tools.

At the optimization level of the new auxiliary program, it is necessary to take into account the local and overall, short-term and long-term, efficacy and toxicity; at the same time, pay attention to early evaluation and program adjustment in the process.

For residual lesions after neoadjuvant, use Biomarker to guide the non-cross-resistance plan for intensive treatment; recognize the prognostic difference of pCR, the prognosis of pCR patients with high initial tumor burden is relatively poor, which may be related to tumor heterogeneity, subclinical lesions, and pathology Underestimation and other factors are related.
For this part of patients, CTC/ctDNA testing can be considered to provide better treatment strategies.

Neoadjuvant treatment is a multi-link and multi-decision process.
The MDT team is beneficial to ensure the standardization of the process implementation and the accuracy of decision-making. Figure 7 Expert profile Professor Xu Yingying/Doctoral Supervisor, Deputy Director of Breast Surgery, First Affiliated Hospital of China Medical University, Specially Appointed Professor of Liaoning Province, Deputy Chairman of the Youth Committee of the Chinese Medical Association Oncology Branch, Secretary of the Breast Oncology Group, Chinese Medical Association Oncology Branch Member of the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association Deputy Chairman of the Youth Committee of the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association Member of the Youth Council of the Chinese Anti-Cancer Association Director of the Youth Committee of the Oncology Branch of the Liaoning Medical Association MD Anderson Cancer Center Visiting scholar presided over the National Nature There are 3 scientific fund projects and 5 provincial and ministerial projects.

Won 5 provincial and ministerial science and technology progress awards, and the 9th Liaoning Youth Science and Technology Award.

Selected in the "Hundred" level of Liaoning Province's Hundred, Thousand, Thousand Talent Project in 2018