April 12, 2024

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New clinical classification and treatment strategies of HER2-positive breast cancer

New clinical classification and treatment strategies of HER2-positive breast cancer


Interpretation of the review: New clinical classification and treatment strategies of HER2-positive breast cancer

New classification criteria for HER2-positive breast cancer may help more patients achieve cure.



Breast cancer is the most common malignant tumor worldwide. With the widespread application of mass screening and mammography, the opportunities for early diagnosis of breast cancer are increasing. About 15-20% of breast cancers show HER2 gene amplification or protein overexpression [1] .

HER2-targeted drugs are constantly being innovated and widely used in clinical practice. More and more HER2-positive advanced breast cancers have achieved long-term disease-free status (NED), which is similar to a cure.

However, currently based on the 8th edition of the American Joint Committee on Cancer (AJCC) breast cancer staging system, HER2-positive breast cancer with distant metastases is classified as stage IV, an incurable category.

A recently published review innovatively proposes to divide HER2-positive breast cancer into four categories, so as to more concisely distinguish early-stage HER2-positive breast cancer, and at the same time identify as accurately as possible in stage IV patients who have potential cure after active individualized comprehensive treatment Opportunity group, so that more cancer patients can be cured [2] .

The important content is now captured and organized as follows for reference.




HER2-positive breast cancer: The current taxonomy needs to be improved

In the two decades since the introduction of trastuzumab, most patients with HER2-positive early-stage breast cancer have been cured, and patients who have not been cured have also experienced significant and durable improvements in quality of life and overall survival. In patients with HER2-positive local metastases (less extensive/small burden of metastatic disease) or extensive, locally recurrent disease, or patients with metastatic disease but exceptional responses (achievement of durable complete remission), the cure rate also exceeds 30% [3,4] .


The biggest highlight of the 8th edition of the AJCC breast cancer staging system is that four biological indicators including HR, HER2, tumor histological grade and Ki-67 are included in the newly added prognostic staging information as an important supplement to the TNM anatomical staging.

In some solid tumors (eg, colorectal cancer and non-small cell lung cancer), current AJCC staging criteria take into account the site and extent of distant metastatic disease to provide a more accurate prognostic assessment.

However, in breast cancer, the widespread use of HER2-targeted drugs, especially ADCs, has weakened the impact of various tumor gene mutations and signaling pathway changes on the prognosis of HER2-positive breast cancer, and also weakened the role of factors such as tumor size and lymph node metastasis data in breast cancer.

The role of prognosis in HER2-positive early breast cancer.


HER2-positive early-stage breast cancer can be effectively cured with existing therapies, and the staging (or classification) and development of treatment strategies should be differentiated from tumor types with poor prognosis (eg, pancreatic cancer, triple-negative breast cancer).

Therefore, it is necessary to develop a new standard to define different prognostic subgroups, develop individualized treatment goals for patients, and improve the overall cure rate of HER2-positive breast cancer.




HER2-positive breast cancer: Clinical four classifications help individualized diagnosis and treatment

The new classification system proposed in this review is based not only on traditional anatomy, clinical features, and tumor biology, but also combines available treatment options and outcomes (such as long-term complete remission, high cure rate), toxic side effects, and tolerability to classify HER2-positive tumors into tumors. There are four types of breast cancer:


New clinical classification and treatment strategies of HER2-positive breast cancer

Figure 1. Four clinical classifications and management strategies for HER2-positive breast cancer


Group A: Early breast cancer with tumor ≤3 cm and negative lymph nodes . About 60% of breast cancer patients belong to this group, and the cure rate exceeds 95% [5] . Treatment strategies include de-escalation therapy (such as 12 cycles of weekly paclitaxel + 1 year of trastuzumab) and avoiding the risk of late toxicity [5,6] .

Neoadjuvant therapy may be considered for HR-negative breast cancer patients with large (>2cm) or medium-sized (0.8cm-2cm) tumors in this group [7] . Low-risk patients (such as grade I, strong ER/PR positive, low Ki-67, tumor size <0.8cm) may consider participating in clinical trials of targeted therapy regimens without chemotherapy, especially if HER2 is overexpressed but heterogeneous Low patients [8] .



Group B: locally advanced or early breast cancer with tumor >3cm . Patients in this group should receive neoadjuvant therapy with trastuzumab + pertuzumab (HP) combined with chemotherapy (AC followed by THP, THP followed by AC, TCHP, or ADC followed by THP in clinical trials).

Patients who achieved pathological complete remission (pCR) should continue to complete 1 year of HP treatment. Patients with residual disease after anti-HER2 neoadjuvant therapy should consider using T-DM1 or participate in clinical trials and use new treatment options [9] .

HR-positive patients should receive adjuvant endocrine therapy for at least 5 years after completion of adjuvant chemotherapy. Treatment of these patients with the goal of cure is recommended, with standard care and a treatment strategy guided by response to treatment.


Group C: Patients with locally recurrent tumors, newly diagnosed, distant or early limited metastasis (solitary or oligometastasis), and extensively metastatic breast cancer.

Despite conventional wisdom that patients with metastatic breast cancer are refractory to conventional therapy, appropriate treatment can leave some patients with long-term NED.

In this context, it becomes a challenge to identify the best potentially curable population, including determining which populations can receive precisely targeted therapy for tumor-specific weaknesses, or benefit from escalating strategies, while avoiding overtreatment of incurable patients. treat.


These patients have the following characteristics:

(1) local or regional recurrence, including contralateral axillary lymph node recurrence or sternal metastasis, local recurrence treatment principles should be adopted;

(2) new, late or early limited metastases, including single metastases (such as brain, single metastases in bone or liver) and oligometastasis; 

(3) special responders who achieved long-term complete remission with a few cycles of chemotherapy combined with anti-HER2 therapy and/or targeted chemotherapy for extensively metastatic breast cancer.


Although this group of patients has the hope of cure, the heterogeneity of tumor and host biology is high, so the treatment plan should accurately target the tumor-specific weaknesses, otherwise intensive comprehensive treatment can be considered.

Consistent with regimens for locally advanced breast cancer, multidisciplinary treatment includes non-cross-resistant systemic therapy [TCHP is preferred if initial (neo)adjuvant therapy is AC followed by THP (or THP followed by AC); sequential 4-8 cycles of T-DXd], followed by local therapy (e.g. surgery and/or radiation therapy) and an optimal consolidation/maintenance regimen based on treatment response, as long as the patient is in good physical condition and agrees to an intensive treatment strategy.

For slowly progressive oligometastatic disease, radical surgery or radiotherapy (eg, stereotactic radiosurgery) can be considered on an individual basis without intensive chemotherapy.


Group D: Advanced breast cancer patients with extensive metastatic breast cancer who did not respond well to initial systemic therapy and who were in poor general condition.

This group of patients is generally considered incurable with conventional therapies, but can achieve long-term survival. Tumors often develop resistance mechanisms to HER2-targeted therapies.

Palliative care regimens and their impact on quality of life should take into account long-term factors, including long-term treatment and accumulation of toxic side effects.

After receiving a certain cycle of chemotherapy combined with anti-HER2 therapy, HR-positive patients should be switched to endocrine therapy.

Surgery and radiation therapy can be considered for palliative care, and patients with pathological fractures (actual or impending) may benefit from internal fixation.

Patients with spinal metastases requiring surgery are often considered for dissection followed by stereotactic radiation therapy.

Brain metastases become very common in later stages of treatment, and many tumors are amenable to stereotactic radiation therapy (eg, Gamma Knife, CyberKnife), thereby avoiding whole-brain radiation therapy.



HER2-Positive Breast Cancer Treatment-Related Challenges

Cytotoxic chemotherapy can overcome heterogeneous tumor cell clones and is an important treatment for HER2-positive breast cancer.

This is even more important after the advent of HER2-targeted ADCs. A variety of chemotherapy drugs have been shown to have synergistic effects with HER2-targeted drugs, especially monoclonal antibodies.

For breast cancer, especially patients with small-volume, oligometastatic disease, more aggressive chemotherapy management may be required.

The development of ADC drugs such as T-DM1 and T-DXd is a major breakthrough for the treatment of HER2-positive breast cancer. The use of non-targeted chemotherapy may be reduced in the future.


Although immunotherapy with PD-1/PD-L1 inhibitors was unsuccessful in HER2-positive breast cancer, antibody-dependent cell-mediated cytotoxicity from trastuzumab, pertuzumab, and ADC Played a key role in eradicating micrometastatic lesions, enhancing immune surveillance, and preventing late relapse.

An immune-active breast cancer microenvironment, such as the expression of CD8+ tumor-infiltrating lymphocytes, is associated with a favorable prognosis in patients with HER2-positive breast cancer.

Peptide vaccine GM2 combined with trastuzumab and new immunostimulatory antibody-drug conjugates may become effective immunotherapy in the future.


Late recurrence of early breast cancer (often occurring more than 5 years after initial diagnosis and treatment) is a significant clinical problem, especially in HR-positive patients [10 ] .

Late metastatic recurrence is the result of reactivation of dormant residual tumor cells, and currently there is a lack of specific and efficient targeting of minimal residual disease (dormant diffuse tumor cells or micrometastases) and dormant metastatic lesions treatment strategy.

Advanced liquid biopsy diagnostic methods (such as circulating tumor DNA detection and analysis) will be applied to minimal residual lesions to more accurately identify, characterize, and monitor the status of residual lesions.


Molecular imaging (such as novel antibody-conjugated nuclear probes) and liquid biopsy are noninvasive tools for breast cancer screening, guiding treatment and evaluating efficacy, and exploring drug resistance mechanisms.

These methods can facilitate the development of highly efficient and low-toxic individualized diagnosis and treatment strategies.

Researchers are actively conducting clinical validation work on novel imaging techniques and biomarkers to determine whether they can effectively detect limited metastatic breast cancer, thereby providing more accurate and sensitive tools for the diagnosis and treatment of breast cancer patients .


By detecting circulating tumor cells and circulating tumor DNA, the presence or absence of metastatic disease can be identified before the patient has obvious symptoms and helps to distinguish the early stages of oligometastatic or extensive metastatic disease.

Circulating tumor DNA analysis can also help determine whether HER2-positive breast cancer treatment can be discontinued in patients with minimal residual disease and special responders.

Meanwhile, HER2-targeting antibodies combined with nuclear probes can be used to guide anti-HER2 therapy for brain metastases.

The risk of late toxicity in long-term survivors of early-stage breast cancer may be reduced by de-escalating therapy and an adaptive approach to molecular imaging.


For patients with higher cure rate among HER2-positive breast cancer patients (group A), systemic treatment, cardiovascular complications and comorbidity management are the directions that are being actively explored and should also be clinically crucial factors. Diet and physical activity are just as important for breast cancer survivors.

Additionally, among breast cancer survivors, cancer treatments (such as targeted therapy, chemotherapy, and radiation therapy) and modifiable factors (including diabetes, obesity, physical inactivity, poor diet, and smoking) increase the risk of cardiovascular disease [11 ] .

These cardiovascular disease risk factors should be addressed promptly. For example, anthracyclines should be avoided in patients with uncontrolled hypertension, while metformin is recommended in patients with type 2 diabetes mellitus and HER2-positive breast cancer if there are no contraindications [12,13] .


Adjusting strategies according to risk and treatment response is an important direction for individualized treatment of HER2-positive breast cancer.

In patients with HER2-positive early breast cancer with residual invasive lesions after completion of neoadjuvant therapy, adjuvant T-DM1 therapy reduced the risk of recurrence or death by 50% compared with trastuzumab alone [9 ] .

The phase II PHERGain study used 18 F-FDG PET/CT to evaluate the early pCR status of HER2-positive early breast cancer patients in response to HP neoadjuvant therapy, and adjusted the strategy according to the results to de-escalate treatment.

The results showed that 37.9% of the patients achieved pCR [ 14 ] , suggesting that PET/CT can identify responders who may not require chemotherapy or anti-HER2 therapy.


HER2-positive breast cancer patients with de novo disease, extensive immune infiltration, low disease burden, and strong HER2 overexpression are more likely to achieve durable treatment responses; however, these patients are currently excluded from curative therapy due to the presence of distant metastases. out of scope.

The efficacy of novel HER2-targeted drugs has been significantly improved, and the possibility of curative treatment should be explored.

The review proposes that cure for HER2-positive metastatic breast cancer is defined as a complete remission as assessed by imaging studies lasting at least 10 years, especially for HR-positive patients.


Achieving complete remission is a key predictor of long-term outcome. Due to the complexity and heterogeneity of tumor biology and tumor microenvironment in group C patients, precision therapy targeting tumor-specific weaknesses is a better strategy; otherwise, intensive therapy is recommended with extreme caution, by using novel , highly effective anti-HER2 drugs or a combination of effective drugs to maximize the chance of achieving complete remission.





The remarkable success of current systemic therapy for HER2-positive breast cancer has challenged the traditional staging system.

Traditional staging systems are based primarily on tumor size, lymph node involvement, and the presence or absence of overt metastatic disease.

Improvements in long-term survival and the quest for a cure are no longer limited to patients with early-stage breast cancer, but are expanding to patients with extensive metastases with limited metastases and good responses to treatment.

For tumor types with high cure rates (group A), it is important to avoid long-term toxic side effects in survivors when treatment regimens are initially formulated.

Cure of locally advanced breast cancer with standard and response-guided strategies (arm B).

For patients with limited-metastatic cancer who are hopeful for cure, precision therapy targeting tumor-specific weaknesses can be used (Group C).

For incurable patients (group D), it is recommended to monitor treatment compliance and long-term treatment toxicity.

At the same time, patients with extensively metastatic HER2-positive breast cancer who achieved exceptional responses to treatment were also proposed to be included in Group C, a novel response-guided dynamic classification.


Today, most patients with HER2-positive breast cancer can be cured. For incurable patients, the goal of treatment is to prolong survival and maintain long-term quality of life. The classification system proposed in this review needs further evaluation and refinement, but this classification may provide a reference for other tumors with high cure rates (eg, nasopharyngeal carcinoma, prostate cancer).







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[8] He X, Ji J, Tian M, et al. Long-Term Survival Analysis of Adjuvant Chemotherapy with or without Trastuzumab in Patients with T1, Node-Negative HER2-Positive Breast Cancer. Clin Cancer Res. 2019 Dec 15;25 (24): 7388-7395.

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[10]Pan H, Gray R, Braybrooke J, et al. 20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years. N Engl J Med. 2017 Nov 9;377(19):1836-1846.

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[12] He X, Ji J, Dai X, et al. Association of Cardiovascular Disease Risk Factors with Late Cardiotoxicity and Survival in HER2-positive Breast Cancer Survivors. Clin Cancer Res. 2021 Oct 1;27(19):5343-5352 .

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(source:internet, reference only)

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