Whether the detection of breast cancer 21 gene expression is suitable for patients with low expression of HER 2

Foreword

The detection of breast cancer 21 gene expression level is used for patients before adjuvant therapy, and its detection significance is mainly to predict the prognosis and chemotherapy efficacy. One limiting condition for the population to which the guidelines recommend is that it be negative for HER2 (HER2-). Approximately two-thirds of hormone receptor positive (HR+) breast cancers and one-third of triple negative breast cancers (TNBC) show HER2 low expression (HER2-low). Antibody-coupled agents (ADCs), such as trastuzumab (T-Dxd), are effective in advanced patients with HER2-low. Whether the detection of breast cancer 21 gene expression is suitable for patients with low expression of HER 2 ?

Significance

The probability of distant recurrence within 10 years in patients treated with tamoxifen alone after surgery is approximately 15%, and if chemotherapy is provided to everyone, 85% of patients receive excessive chemotherapy. Therefore, through the training set of 447 breast cancer patients, the researchers selected 16 cancer-related genes and 5 reference genes from 250 candidate genes, detected the expression levels of 21 genes by multiplex fluorescent PCR, and calculated the recurrence risk score (RS) by using the set coefficients and algorithms. This is the prototype of the 21 gene detection Oncotype Dx.

The first application of the detection is a prognostic indicator. The NSABP B-14 study analyzed 668 lymph node-negative (N0) patients treated with tamoxifen. The 10-year distant recurrence risks in the low-risk (RS < 18), medium-risk (18 ≤ RS < 31) and high-risk (RS≥31) groups were 6.8%, 14.3% and 30.5%, respectively, and the difference was significant between the low-risk and high-risk groups (P < 0.001). In patients with both N0 and lymph node positivity (N+) included in the TransATAC study, RS values were found to stratify the 9-year risk of distant recurrence.

Another very important function of the detection is to predict the efficacy of chemotherapy. NCCN preferably recommends the detection for prognosis and chemotherapy efficacy prediction, while other gene expression analyses can provide prognostic information, but it is unknown whether they can predict chemotherapy benefit. The detection has the most perfect evidence system, and multiple large-scale and prospective clinical studies confirm its effectiveness. The detection on chemotherapy efficacy tips see below. Notably, the TAILORx and RxPONDER studies set new thresholds for indicating chemotherapeutic efficacy, but did not adjust the thresholds that divide the risk of recurrence. Therefore, the threshold of 21 gene is different in different application scenarios.

Applicable population

The detection is suitable for patients with non-metastatic invasive breast cancer and is tested after surgery and before adjuvant treatment. The NCCN guidelines strongly recommend the detection of 21 genes in two populations and polygene expression profiles in one. Specific restrictions are shown in the table below. For premenopausal N1 patients who have benefited to different degrees from chemotherapy, it is only recommended to test the multi-gene expression profile before adjuvant treatment to assess the prognosis.

The above restrictive conditions proposed by NCCN are supported by clinical trials. First, although most studies include tumors of different sizes, the proportion of tumors that are 4 cm or more is small. Median tumor size was 1.5 cm for TAILORx studies and 1.9 cm for PLAN B studies. The TAILORx study (which included only N0 patients) excluded patients with tumors ≤0.5 cm, who had a low risk of recurrence and were only recommended for adjuvant endocrine therapy by the NCCN guidelines. SWOG-8814 included 4.6% of patients with tumors > 5 cm, and tumors > 5 cm were associated with chemotherapy benefits.

Clinical studies of 21 gene rarely include more than four lymph node-positive patients. The PLAN B study included 4.6% of N2 patients and 1.4% of N3 patients who were directly assigned to the chemotherapy group. Study SWOG-8814 included 38.1% of patients with more than four positive lymph nodes, and the study found that these patients had an increased risk of recurrence, stratified with N1 patients. Moreover, the positivity of more than four lymph nodes was significantly correlated with the chemotherapy benefit (p=0.015). Therefore, NCCN guidelines directly recommend adjuvant chemotherapy plus endocrine therapy for N2-3 patients (ovarian suppression therapy for premenopausal patients).

Clinical studies of the 21 gene almost exclude HR-(ER- and PR-) patients, and HR- is also not related to endocrine therapy. The PLAN B study included 2.4% of HR patients who were directly assigned to the chemotherapy group. The MINDACT study of the 70 gene included 11.6% of HR- patients, and the study found that 95.8% (745/778) of HR- patients were at high genomic risk, and 96.4% (617/640) of TNBC patients were at high genomic risk. It indicated that HR was a high risk for patients, and the significance of detecting multi-gene expression profile was limited.

Breast cancer with HER2 amplification or overexpression accounts for 15%–20% of all cases, and has been reported as 25%–30% in early studies. Compared to HER2- tumors, the prognosis is worse and more aggressive. An early NSABP B-14 study included 55 patients (8.2%) with HER2 amplification. Among patients with HER2-amplified and non-amplified tumors, the percentages of patients with no distant recurrence within 10 years were 75.0% and 86.0%, respectively (p = 0.08). HER2 amplification was mainly concentrated in patients with high RS values. Therefore, patients with HER2 positivity have a poor prognosis and are not suitable for 21 gene detection.

21 gene can be used in patients with HER2 low expression

At present, the most authoritative guideline for HER2 detection of breast cancer is the 2018 ASCO/CAP HER2 detection guideline. ASCO/CAP uses the term "HER2 negative" for "tumors with an immunohistochemical (IHC) score of 0, 1+ or 2+/ in situ hybridization (ISH) not amplified".

Approximately two-thirds of HR+ breast cancers and one-third of TNBC show HER2-low (a HER2 IHC score of 1+ or 2+/ISH not amplified), and ADC-based drugs such as T-Dxd are effective in advanced-stage patients with HER2-low. NCCN Breast Cancer Guideline 2023 v1 included HER2-low in the guideline, but only mentioned in a footnote to date that "the difference between HER2 IHC 0 and 1+ is currently clinically relevant in metastatic conditions because patients with negative HER2 1+ or 2+/ISH may be eligible for treatment at a non-amplification level of HER2."

The ASCO/CAP guidelines were updated in 2023 to include a few points. Invasive breast cancer that is "HER2 negative" is more specifically considered to be "HER2 protein overexpression/gene amplification negative". It is too early to change the reporting term for HER2-low. There is no evidence that HER2-Low is a new or redefined breast cancer subtype with different prognostic or prognostic implications. The results of HER2 IHC 0 and HER2-low tests in patient samples also appear to be unstable, and cases of IHC 0 may also have low levels of HER2 protein expression by more sensitive tests. The ESMO expert consensus on HER2-low also mentions that the term "HER2 negative" has been used for more than two decades to define tumors lacking HER2 overexpression and/or amplification. This is a well-established term that has been precisely defined in the 2018 ASCO/CAP guidelines and should not be modified at this time.

HER2- patients were included in both TAILORx and RxPONDER studies of the 21 gene. TAILORx study HER2- Criteria were "FISH assay without amplification or IHC(DAKO Herceptest)0 or 1+". The criteria for the RxPONDER study was "according to ASCO/CAP 2013 guidelines: IHC 0, 1+ or IHC 2+ and no amplification by FISH". It can be seen that important clinical trials with 21 gene have included patients with HER2-low, and 21 gene can be used in patients with operable invasive breast cancer with HER2-low.

21 gene scalability applications

In addition to the two mature applications of prognostic implications and chemotherapeutic efficacy prediction mentioned above, there are some exploratory and expansive applications of the 21 gene. NCCN guidelines state that gene 21 is the only polygenic assay available for pathological prognostic staging, with a T1-2 N0 M0 HER2-negative, ER-positive tumor, and a pathological prognostic stage of IA if RS < 11.

Two retrospective studies are exploring the application of 21 gene in radiotherapy efficacy prediction. A retrospective study of SWOG-8814 analyzed N1 patients who did not receive radiotherapy after operation, and the 10-year local recurrence risk (LRR) of low-risk group and medium-risk group were 1.5% and 11.1% (P = 0.051), respectively, indicating that the detection of 21 gene expression level can evaluate the LRR risk of breast cancer patients to some extent, and the patients in the low-risk group may be exempt from adjuvant radiotherapy after operation. HR+ HER2- Application of multi-gene testing for postoperative adjuvant treatment of early breast cancer: Experts' consensus recommends that for patients with low risk (RS < 18) indicated by 21 gene testing results, radiotherapy has no significant benefit, and radiotherapy is recommended to be exempted; 21 The results of gene detection indicated that for patients with high risk (RS≥18 points), radiotherapy would bring significant benefits and reduce the risk of local recurrence. Radiotherapy was recommended (recommended grade: 2B).

A secondary analysis of the RxPONDER study showed a 5-year LRR rate of 1.7% in patients with HR+, HER2-, and 21 gene scores ≤25, and N1 breast cancer, respectively. Regional lymph node radiotherapy did not bring benefits for local recurrence and survival without invasive recurrence, suggesting that 21 gene detection can help to predict the benefits of regional lymph node radiotherapy. The study was also cited in the CSCO guidelines, but noted that high-level evidence-based medical evidence was still needed.

The TransNEOS study analyzed 295 breast cancer patients with T1c-2 N0 M0, ER+, and HER2- receiving neoadjuvant endocrine therapy, with a median age of 63 years. Patients with RS < 18 had significantly higher clinical response rates compared with patients with RS≥31 (P < 0.001). RS was significantly associated with breast-conserving therapy following neoadjuvant letrozole (p=0.009). Another study included 989 breast cancer patients with T1-3, ER+ and HER2- neoadjuvant chemotherapy, with a median age of 54.6 years. Forty-two patients (4.3%) achieved complete pathological response (pCR), and there was a significant correlation between pCR and high RS (OR=4.87). Based on these two studies, the NCCN guidelines indicate in footnotes that operable patients with N0, ER+, and HER2- postmenopausal neoadjuvant therapy should have their gene expression profiles detected and their neoadjuvant efficacy evaluated.

Summary

Detection of 21 gene expression level in breast cancer patients before adjuvant therapy can prompt prognosis and predict chemotherapy efficacy. Patients with HR+, HER2-, pT1-3, pN0, or pN1 (excluding ≤0.5 cm and N0) are recommended by the NCCN guidelines for whom HER2- includes HER2-0 and HER2-low. NCCN guidelines state that the 21 gene can be used for pathological prognosis staging in patients with T1-2 N0 M0, ER+, and HER2-. At present, in some studies, the 21 gene is used for predicting the efficacy of adjuvant radiotherapy and neoadjuvant endocrine and chemotherapy. Fushuo is committed to providing the most innovative products and services for the individualized and precise medical detection of tumors, and continuously updates the existing products.

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