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The latest advances in early breast cancer treatment, these clinical studies have to know! Professor Jin Feng

 Last Update: 2022-11-15
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Early breast cancer is the most important chance for
breast cancer patients to achieve high-quality survival.
In recent years, a large number of clinical studies on early-stage breast cancer have been published, which have influenced the clinical practice
of early-stage breast cancer.
At the just-concluded 17th Shanghai International Breast Cancer Forum (SIBCS), Professor Jin Feng from the First Affiliated Hospital of China Medical University summarized the important research
that has recently changed the clinical practice of early-stage breast cancer.

Four major studies to optimize neoadjuvant/adjuvant therapy

01Based on the PATTERN study, NCCN guideline 2022V1 recommends TNBC platinum-containing adjuvant chemotherapy regimen
for the first time.

Professor Jin said, "In the past, there has been controversy about the efficacy of platinum in neoadjuvant/adjuvant therapy for early-stage breast cancer, mainly because there are too few
studies on platinum for adjuvant therapy for breast cancer.
"Recently, the PATTERN study published by Professor Shao Zhimin of Fudan University Cancer Hospital in JAMA Oncology for the first time confirmed that purple shirt alcohol combined with carboplatin (PCb) regimen is an effective adjuvant chemotherapy regimen
for patients with operable triple-negative breast cancer (TNBC).

The PATTERN study explored the efficacy of the PCb regimen compared with the current guideline recommended cyclophosphamide + epirubicin + fluorouracil (CEF-T) regimen as adjuvant therapy after early TNBC surgery, and the primary endpoint of the study was disease-free survival (DFS).

。 The results of the study showed that the PCb regimen improved DFS at 5 years of early operable TNBC by 6.
2% (86.
5% vs 80.
3%, HR=0.
65, 95% CI: 0.
44-0.
96, P=0.
03) compared with the CEF-T regimen, and the results of distal disease-free survival (DDFS) and recurrence-free survival (RFS) were consistent (Figure 1).

Fig.
1 The results of PATTERN study results (Source: Professor Jin Feng ppt) and the results of the subgroup analysis of the study showed that young, high-grade tumors were more inclined to PCb regimens, and homologous recombinant repair defects (HRD)
could benefit
more from platinum-based therapy.

02 Based on KEYNOTE-522, the CSCO-BC guideline recommends chemotherapy combined with PD-1 inhibitors as a level III recommendation
for neoadjuvant therapy for TNBC.

KEYNOTE-522 is the first prospective, randomized, placebo-controlled, phase III study
of pembrolizumab in the neoadjuvant and adjuvant therapy of early TNBC.
TNBC patients enrolled in T1c N1-2 or T2-4 N0-2 were divided into experimental group and control group according to a ratio of 2:1, the control group was treated with placebo combined with chemotherapy, the experimental group received the same regimen of chemotherapy plus pembrolizumab, and the patients in the two groups received placebo or pembrolizumab for 9 cycles
after surgery.
The study was designed with a dual-endpoint study (Figure 2), with primary endpoints including neoadjuvant pathologic complete response (PCR, ypT0/Tis N0) and event-free survival (EFS).

Fig.
2 KEYNOTE-522 STUDY DESIGN (SOURCE PROFESSOR JIN FENG COURSEWARE)
RESEARCH RESULTS SHOW THAT 1.
Compared with placebo combined with neoadjuvant chemotherapy, pembrolizumab combined with neoadjuvant chemotherapy PCR is significantly improved
.
2.
Compared with neoadjuvant chemotherapy alone, pembrolizumab combined with neoadjuvant chemotherapy sequential pembrolizumab adjuvant therapy can significantly increase EFS (36 months).

And the results of the 2022 ASCO study showed that pembrolizumab combined with chemotherapy can improve the EFS of patients with RCB0, 1 and 2, of which the RCB-2 category has the most significant
benefit.

03Based on PHEDRAP research, the CSCO-BC guideline (2022 version) takes H+TKI as the level II recommendation for neoadjuvant therapy for HER-2-positive breast cancer

PHEDRA is a multicenter phase III study
led by Professor Wu Jiong of Fudan University Cancer Hospital on the neoadjuvant treatment of HER2-positive early or locally advanced breast cancer with pyrrotinib combined with trastuzumab and docetaxel (Py+TH).
The study was divided into a 1:1 ratio between the experimental group and the control group, which received a placebo plus docetaxel and trastuzumab (TH) regimen, and the experimental group received the Py+TH regimen
.
The results showed that the Py+TH regimen significantly increased the tpCR rate (41.
0% vs22.
0%, p<0.
0001)<b12> compared with the TH regimen.

04NeoCART study: NCCN guideline 2022V1 for the first time cites China's original innovative adjuvant clinical research to provide new evidence
for neoadjuvant therapy for TNBC patients.

The NeoCART study is an exploration of platinum-based neoadjuvant therapy in China, which was carried out by the team of Professor Wang Heng of Guangzhou Provincial People's Hospital, which showed that compared with the standard regimen (epirubicin plus cyclophosphatamide sequential docetaxel, EC-D), docetaxel + carboplatin regimen (DCb) can improve the pCR rate of neoadjuvant chemotherapy in TNBC patients, and the two groups of EFS and OS are similar
.

Strengthen treatment plans to help "ladder" adjuvant treatment

01 Based on the Olympia A study, CSCO-BC guidelines recommend 1.
Adjuvant therapy of non-pCR after neoadjuvant therapy of TNBC, 2.
Follow-up treatment of TNBC (lymph node positive or tumor > 2cm) adjuvant therapy: BRCA mutation olaparib is recommended for grade II (currently olaparib has not been approved for indications in China and should be carefully considered).

The Olympia A study focused on the efficacy and safety
of olaparib as an adjuvant therapy for early-stage breast cancer.
The study included patients
with early-stage breast cancer who had received topical therapy and neoadjuvant/adjuvant chemotherapy.
The results of the study show that:

With a median follow-up of 2.
5 years, adding olaparib adjuvant intensive therapy to 1 year after standard therapy significantly improved 3-year survival without invasive disease (iDFS) and DDFS in patients with early-risk BRCA germline mutation HER2-negative breast cancer (Figure 3)
compared with placebo.

Figure 3 Olympia A research results (source Professor Jin Feng's courseware)

A median follow-up of 3.
5 years, compared with placebo, significantly improved 4-year OS
in patients with early-risk BRCA germline mutation HER2-negative breast cancer after 1 year of adjuvant intensive therapy with olaparib.

02 SYSUCC-001Study: NCCN Guidelines 2022V1 first cited the low-dose maintenance regimen of capecitabine in the SYSUCC-001 study

Professor Yuan Zhongyu of Sun Yat-sen University Cancer Center conducted the SYSUCC-001 study
in 2010 to evaluate the efficacy and safety of low-dose capecitabine maintenance therapy after TNBC standard treatment.

The findings showed that low-dose capecitabine beat chemotherapy maintenance therapy significantly prolonged DFS and DDFS in patients with early TNBC, with a median follow-up of 61 months, increasing DFS from 73.
0% to 82.
8% (HR: 0.
64, 95CI%: 0.
42-0.
95) and 5-year DDFS from 75.
8% to 85.
8% in the capecitabine beat chemotherapy group compared with placebo.
（HR：0.
60，95%CI：0.
38-0.
92，p=0.
02）
。

03MonarchE study: Domestic and foreign guidelines unanimously recommend that for patients with HR+HER- high risk (≥ 4 positive lymph nodes or 1-3 positive lymph nodes and at least one of the following: and tumor size ≥5 cm, histological grade 3 or central Ki-67≥20%) breast cancer, abeccilil adjuvant therapy can be considered for 2 years
after surgery.

At the meeting, Professor Jin Feng introduced: "CDK4/6 inhibitors have good efficacy in first-, second-line and post-second-line breast cancer, while the efficacy of CDK4/6 inhibitors in early-stage breast cancer is unknown
.
The MonarchE study further explored the efficacy of CDK4/6 inhibitor (abecilib) combined with endocrine therapy in the adjuvant therapy of HR+/HER2-high-risk early stage breast cancer (Figure 4).

Fig
.
4 MonarchE research protocol (Source: Professor Jin Feng courseware)
The results of the final efficacy analysis of MonarchE research show that compared with endocrine therapy alone, abeclib combined with endocrine therapy can significantly reduce the risk of invasive disease by 25.
3% and the risk of distant recurrence by 28.
3%.

And the benefits of iDFS and DRFS from abecilib in combination with endocrine therapy persist.

04SUCCESS-A study: CACA-CBCS guidelines (2021 edition) do not currently recommend bisphosphonates in patients without radiographic evidence of bone metastases and in patients with extraosseous metastases without evidence of bone metastases

The SUCCESS-A study is a clinical study comparing different duration of bisphosphonates for 5 and 2 years of survival with zoledronic acid therapy in patients with adjuvant chemotherapy after surgery for early-stage node-positive or high-risk node-negative breast cancer
.
The study showed that for patients with adjuvant chemotherapy after surgery for early-stage breast cancer, there was no significant improvement in survival outcomes and a higher incidence of adverse time, especially bone pain and arthralgia
, compared with 5 years of treatment with zoledronic acid compared with 2 years.
Therefore, the duration of zoledronic acid in patients with high-risk postoperative chemotherapy for early breast cancer can be reduced to 2 years
.

Polygenic tools adjuvant chemotherapy "down the ladder"

01CSCO-BC Guidelines (2022 Edition) recommend MammaPrint testing

The RxPONDER study showed that adjuvant chemotherapy reduced the risk
of recurrence by 46% in postmenopausal breast cancer patients with 1-3 lymph node metastases and a 21 gene score of 0-25.
Postmenopausal patients do not benefit significantly from chemotherapy and can be dispensed with
.
The MINDACT study showed that for some patients with high clinical risk, 70 genetic test results can screen some patients to avoid chemotherapy
.

The RxPONDER study focuses on the recurrence score of 21 gene breast cancer detection, which can be used clinically for the efficacy
of HR+HER-2-lymph node 1-3 adjuvant therapy (endocrine and/or chemotherapy) for early-stage breast cancer 。 The results of the study showed that at a median follow-up of 5.
3 years, endocrine therapy alone was similar to IDFS in postmenopausal women (91.
9% vs.
01.
3%, HR: 1.
02, 95CI% 0.
82-1.
26, p=0.
89) and postmenopausal IDFS (91.
9% vs.
01.
3%, HR: 1.
02, 95CI% 0.
82-1.
26, p=0.
89) compared with chemotherapy combined with endocrine therapy.

Therefore, it can be concluded that HR+HER-2-postmenopausal women with 1-3 lymph node metastases and 21 gene scores of 0-25 are exempt from chemotherapy
.

The MINDACT study mainly explores whether adjuvant therapy for early breast cancer with T1-2 or surgical T3 and lymph node metastases ≤ 3 requires chemotherapy
.
This study combines
70-gene monitoring to determine gene risk and Adjuvant Online v8.
0 clinical pathology system to determine clinical risk.
The results of the study showed that with a median follow-up of 8.
7 years, patients with 70 genes at low risk of early-stage breast cancer who were treated with endocrine therapy alone without chemotherapy and had a high
survival without distant metastases (DMFS).
Therefore, for women who are > 50 years old or < 50 years old, the benefits of chemotherapy and no chemotherapy are not high<b23>.

Diverse studies to optimize local treatments

01 Radiotherapy: The CSCO-BC guidelines (2022 edition) recommend a single-week super-fractionation regimen for whole milk after breast-conserving surgery for invasive cancer (pN0) as a level II recommendation (2A evidence).

The FAST-Forward study is a multicenter, non-inferior, randomized, unblinded controlled phase III clinical study evaluating the efficacy of radiotherapy with superfractionated regimens for early-stage breast cancer with the primary endpoint being ipsilateral breast cancer tumor recurrence
.
The results of the study showed that in patients treated with radiotherapy after surgery for early-stage breast cancer, the 5-year local tumor control effect of the 26 gray fractionation 5 times in 1 week was not inferior to that of the 40 gray fractionation regimen in 2 weeks, and the safety of the impact on normal tissue was similar
.

02 Surgical axillary staging: NCCN/ASCO guidelines still recommend SLNB for axillary staging
if the clinical examination is negative for lymph nodes and abnormal imaging (with or without confirmation biopsy).

At the meeting, Professor Jin said that ACOSOG Z0011, EORTC AMAROS, and IBCSG23-01 explored the value of whether to dissect, whether to radiotherapy, and sentinel lymph node biopsy (SLNB) micrometastases, respectively, and the overall results showed that SLNB is the standard surgical axillary management mode for patients with cN0 early breast cancer, and SLN-negative, SLN-positive and axillary low tumor burden can be safely exempted from axillary dissection (Figure 5).

。
Fig.
5 Surgical axillary staging (Source: Professor Jin Feng's courseware).

03 Margins: BMJ meta-study may change international guideline revisions

The current standard for invasive breast-conserving margins is still not consistently recommended by U.
S.
A/ASTRO/ASCO guidelines: no link on tumor
.
However, the large-sample meta-analysis published by the BMJ in 2022 may have implications for revision of international guidelines and changes to clinical practice
.
The results of this study showed that the rate of distant recurrence and local recurrence with negative margin, involvement or proximity to the margin was significantly increased, and systemic therapy could reduce distant recurrence, but could not reduce the rate
of distant recurrence with a margin less than 1 mm.

Finally, Professor Jin concluded at the meeting that in general, there are many studies that change the clinical practice of early-stage breast cancer, and clinicians should maintain the principle of standardized treatment plan so that patients can have a chance of
long-term survival and early cure.

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