HER2 mutation-positive lung cancer



OVERVIEW

Lung cancer patients with positive human epidermal growth factor receptor 2 (HER2) gene mutations caused by various factors, except for the targeted application of HER2 inhibitor therapy, are in general roughly the same as other types of lung cancer have strong metastatic and infiltrative ability, and poor sensitivity to chemotherapy, and are prone to recurrence

Definition

HER2 mutation-positive lung cancer is a molecular typing of lung cancer, and the significance of the typing is to guide clinical diagnostic and therapeutic decisions.

Human epidermal growth factor receptor-2 (HER2), also known as ERBB2 or neu, is a tyrosine kinase receptor in the ERBB/HER family that activates downstream signaling along with other family members such as epidermal growth factor receptor (EGFR).

In non-small cell lung cancer (NSCLC), mutations in the HER2 gene are mainly manifested in the form of gene amplification and mutations (mainly exon 20 insertion mutations), both of which can lead to HER2 activation.

HER2 gene mutations are closely associated with the degree of progression of many epithelial cell cancers, and tumors with HER2 gene mutations exhibit greater metastatic and infiltrative capacity, are less sensitive to chemotherapy, and are prone to recurrence.

HER2 mutations have been identified as a major driver of NSCLC, but have also been suggested as a possible mechanism leading to primary and acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy.

Classification

In NSCLC, HER2 mutations are mainly manifested in two forms, gene amplification and mutation, in addition to HER2 protein overexpression.

Of these, HER2 mutations occur mainly in intracellular structural domains, with the most common type being insertion mutations in exon 20 (48%).

Pathogenesis

HER2 gene mutation or amplification is one of the driver genes in NSCLC, of which the most common genetic variant is HER2 exon 20 insertional mutation, with a mutation rate of 2% to 4% in NSCLC [1].

Patients with HER2 mutations tend to be female, of Asian ethnicity, non-smoking status, and histologically exhibit moderately or poorly differentiated cancers.

Diagnosis

HER2 mutation-positive lung cancers are all tested for HER2 mutations based on the diagnosis of lung cancer, and the results of genetic testing do not affect clinical staging.

Diagnosis basis

The diagnosis of HER2 mutation-positive lung cancer is a further diagnosis based on the diagnosis of lung cancer.

For more information about the diagnosis of lung cancer, please refer to the Lung Cancer article, which only introduces the diagnostic basis of “HER2 mutation-positive”.

Recommendations for testing

HER2 mutation testing should be performed as part of an initial large panel of tests using next-generation sequencing, with priority given to including exon 20 for HER2 mutations.

HER2 mutation testing is recommended whenever possible for patients with unresectable stage III and stage IV NSCLC who meet two or three of the following criteria

Lung adenocarcinoma or adenosquamous carcinoma.

No or only a mild history of smoking.

Females.

[Special Note] HER2 amplification is recommended when resistance to EGFR-TKI develops. In addition, HER2 amplification and expression is recommended for NSCLC in clinical trials.

Assay Subtesting

In NSCLC, there are several methods for detecting HER2 mutations, but no gold standard has been established.

Among the current laboratory assays, HER2 amplification is detected using fluorescence in situ hybridization methods (FISH) or second-generation sequencing (NGS).

HER2 mutations can be detected by Sanger sequencing, amplification blocking mutation system polymerase chain reaction (ARMS-PCR) or NGS.

HER2 protein overexpression is generally detected by immunohistochemistry.

FISH

Advantage: A variety of samples are available, such as tissue samples, cytology samples, etc., and the sample size requirement is low, which is the “gold standard” for gene translocation detection. High-throughput detection (number of genes and types of variants), high sensitivity and specificity, but related to the coverage of the product probe design and bioinformatic analysis capabilities.

Disadvantages: poor cost performance, false negatives for rare variant types. Longer testing period, usually 3 to 5 working days.

NGS

Advantage: Available for a wide range of samples, such as tissue samples, cytology samples, body fluid samples, etc. High-throughput detection (number of genes and types of variants), high sensitivity and specificity, but related to the coverage of product probe design and bioinformatic analysis capability.

Shortcomings: high sample quality requirements, long testing cycle, usually more than 7 working days.

Sanger Sequencing

Advantage: can directly read the given DNA sequence and identify new mutation sites.

Disadvantage: Higher requirements on the content and proportion of tumor cells in the sample, not suitable for small biopsies or cytology specimens.

ARMS-PCR

Advantage: High sensitivity and specificity, easy to perform.

Disadvantages: Unable to recognize new and unknown mutations. When different mutation sites need to be detected, the amount of DNA required for ARMS-PCR increases and the probability of non-specific binding increases accordingly.

Immunohistochemistry

Advantage: short testing period, lower cost.

Disadvantage: only single test, low sensitivity and specificity.

Reminder: Most results of high protein overexpression (IHC3+) are due to HER2 gene amplification, whereas moderate expression (IHC2+) can be found with and without HER2 gene amplification. Therefore, for HER2(2+) results, further FISH testing is usually required.

Treatment

Special Note: The treatment of HER2 mutation-positive lung cancer is generally the same as that of other types of lung cancer, with the difference being the treatment of HER2 targets, which is only described in this section.

Tips: For more information on the overall treatment of lung cancer, please refer to Lung Cancer.

Principles and Objectives

Principles of treatment

The treatment of HER2 mutation-positive lung cancer should adopt the principle of combining multidisciplinary comprehensive treatment (MDT) with individualized treatment.

That is to say, according to the patient’s physical condition, the pathological and histological type and molecular typing of the tumor, the extent of invasion and development tendency, the MDT mode should be adopted, and surgery, radiotherapy, chemotherapy, molecular targeted therapy and immunotherapy should be applied in a planned and reasonable way.

Treatment objectives

Maximize the control of tumor progression, prolong the survival time of patients, and improve the quality of life of patients.

Related drugs

Monoclonal antibody trastuzumab, tyrosine kinase inhibitor (TKI) afatinib, dacomitinib and other drugs have limited efficacy in HER2-mutated NSCLC, so there is no approved targeted drug for HER2 mutation in lung cancer in China.

In recent years, antibody-drug coupling (ADC) has realized the powerful combination of small molecule chemotherapy and monoclonal antibody targeted therapy to reduce toxicity and increase efficacy, which provides a brand new way to realize “precision therapy” for tumors.

In 2022, the National Comprehensive Cancer Network (NCCN) Lung Cancer Guidelines of the United States added the ADC drugs enmetrastuzumab (T-DM1) and trastuzumab-delutecan coupling (T-Dxd, DS-8201) as the recommended treatment for HER2 mutations.

As of October 2022, there are no relevant drugs approved for HER2 mutation-positive lung cancer in China, the following is for scientific reference only, please consult a professional oncologist for the specific treatment plan, and strictly follow the doctor’s instructions, do not purchase and use the drug on your own.

Enmetrastuzumab (T-DM1)

T-DM1 is an anti-HER2 antibody-drug coupling (ADC) consisting of trastuzumab and the cytotoxic microtubule drug emtansine (DM1), a medenosine derivative.

Indications

For use in patients with advanced NSCLC in the presence of HER2 mutation positivity.

Adverse Reactions

The most common adverse reactions include anemia, elevated transaminases, thrombocytopenia, and fatigue.

Therapeutic Effectiveness

Some studies have shown the following effects in patients with locally advanced or metastatic NSCLC who have received prior platinum-containing chemotherapy with T-DM1 monotherapy:

The objective remission rate (ORR) for patients with high HER2 expression (IHC 3+) as assessed by immunohistochemistry (IHC) was 20%, whereas the ORR for patients with low expression (IHC 2+) was zero.

The median progression-free survival (mPFS) was 2.6 and 2.7 months, and the median overall survival (mOS) was 12.2 and 15.3 months in the two groups, respectively [4].

Trastuzumab-delutecan coupling (T-Dxd or DS-8201)

DS-8201 is a 3-part ADC consisting of a humanized anti-HER2 monoclonal antibody, a cleavable tetrapeptidyl linker, and a cytotoxic topoisomerase I inhibitor (DXd).

Applicable Situations

For patients with advanced NSCLC in the presence of HER2 mutation-positive mutations.

Adverse Reactions

The most common adverse events include nausea, vomiting, fatigue, alopecia, neutropenia, anemia, and interstitial lung disease.

Therapeutic efficacy

It has been shown that HER2 mutation-positive NSCLC patients treated with DS-8201 had an ORR of 61.9%, a DCR of 90.5%, and a median PFS of 14.0 months [4].

Pyrrolitinib.

Pyrrolitinib is a small-molecule irreversible tyrosine kinase inhibitor that covalently binds to the ATP-binding site in the intracellular kinase region, comprehensively blocking the formation of HER-family homo-heterodimers, inhibiting tumor cell growth and transmitting the blood-brain barrier.

Piratinib inhibits the activity of HER2 exon 20 mutant NSCLC cells.

Indications

For patients with advanced NSCLC in the presence of HER2 mutation-positive cells.

Adverse Reactions

The most common adverse events include nausea, vomiting, fatigue, alopecia, neutropenia, anemia, and interstitial lung disease.

Therapeutic effects

One study confirmed that this drug has an ORR of 53.3%, a median PFS of 6.4 months, and a median DOR of 7.2 months in patients treated for HER2 insertion mutations [5].

Treatment regimen

Appropriate therapeutic regimens need to be selected based on the patient’s clinical stage.

ADCs (e.g., T-DXd, T-DM1) and TKIs (e.g., pyrrolitinib) are expected to be new treatment options for HER2-altered NSCLC.

Targeted therapy for HER2 overexpressing NSCLC needs further research.

Prognosis

The prognosis of HER2 mutation-positive lung cancer as a whole is roughly the same as that of other types of lung cancer, and is related to a variety of factors, including tumor stage, staging, biochemical indexes, and the patient’s physical health.

Cure

At present, HER2 mutation-positive lung cancer cannot be completely cured, but with active and standardized treatment, some patients can have a chance of clinical cure.

Survival of HER2 mutation-positive lung cancer

Overall, the overall survival of treated HER2 mutation-positive lung cancer patients has improved significantly, and with the introduction of related drugs, patients may obtain longer survival.

Although current guidelines do not recommend first-line treatment for HER2 mutation-positive lung cancer, some studies have confirmed that the second-generation ADC drug DS-8201 has achieved better therapeutic effects, with an ORR of 61.9%, a DCR of 90.5%, and a median PFS of 14.0 months.

The ORR of pyrrolitinib for patients with HER2 mutations was 31.7%, with a PFS of 6.9 months. The above two studies are expected to be new options for the treatment of HER2 mutations [5].

Overall survival of lung cancer

Survival of lung cancer patients can generally be evaluated in terms of 5-year survival rate and depends largely on the clinical stage and pathological type of the tumor at the time of disease detection.

The study comprehensively analyzed the results of several larger-scale statistics from 2000 to 2012, which showed that the 5-year survival rates of non-small cell lung cancer and small cell lung cancer in China for each stage were as follows.

Non-small cell lung cancer

Stage II

Stage IV

5%

Small Cell Lung Cancer

Staged 5-year survival rate

Stage I 45%

Stage I

45%

Stage II 25%

Stage II

25%

Stage III 8%

Stage III

8%

Stage IV 3

Stage IV

3%

Special Reminder

The overall survival time of lung cancer patients can be roughly predicted by the 5-year survival rate (the proportion of patients whose tumors survive for more than 5 years after various comprehensive treatments), and the probability of recurrence after 5 years is very low.

Statistics such as 5-year survival rate and median survival period are only used for clinical research and do not represent the specific survival period of an individual. The individual survival period of a lung cancer patient needs to be determined by combining various factors, and it is recommended to consult the physician consulted.

Prognostic factors

Prognostic factors are factors that have an impact on the overall survival and quality of life of patients.

There is no authoritative independent prognostic factor for HER2 mutation-positive lung cancer, but the prognostic factors common to malignant tumors also apply to HER2 mutation-positive lung cancer.

These factors mainly include the degree of malignancy of the tumor, the stage of the tumor, lymph node metastasis, treatment, and personal constitution.

Patients with a low degree of tumor malignancy have a better prognosis than those with a high degree of tumor malignancy.

In tumor staging, patients belonging to the early clinical stage have a better prognosis than those in the middle or late clinical stage.

Patients with no lymph node metastasis have a better prognosis than those with lymph node metastasis.

Patients with early regular treatment have better prognosis than those with late treatment; patients with good treatment effect have better prognosis than those with poor treatment effect.

Patients with good personal health have a better prognosis than those with poor health.

Daily

Daily considerations for HER2 mutation-positive lung cancer are no different from those for other types of lung cancer.

Just because lung cancer has been treated with surgery, radiotherapy or chemotherapy does not mean that one can let down one’s guard. Active and strict daily management can help patients to better beat cancer.

Daily Management

Mindset and Emotions

Good emotions and mindset cannot be replaced by drugs.

After diagnosis, patients may develop a sense of fear. They may be afraid of pain, abandonment and death. With the encouragement and help from doctors, family and friends, patients need to get rid of the fear as soon as possible, face up to the disease, actively follow the doctor’s instructions, and have an optimistic attitude towards the prognosis.

Family members should pay attention to listening to the patient’s heart, improve the patient’s psychological tolerance, and relieve anxiety symptoms.

It is recommended that the patient’s family give support so that the patient can face the surgery and other treatments positively with a good mindset.

During the period between treatments and after treatment, family members are advised to encourage the patient to do work and household chores that are within his/her ability to reintegrate into his/her social role.

Healthy lifestyle

For lung cancer patients, a healthy lifestyle can reduce recurrence and lower the risk of death.

Ensure sleep: Patients should rest more and ensure enough sleep.

Maintain a healthy diet: Eat a diet rich in vegetables, fruits and whole grains, reduce the intake of excessive sugar, fatty foods, and red and processed meats, and minimize alcohol intake.

Maintain a healthy weight: Be appropriately active, such as slow walking, tai chi, qigong and breathing exercises, and avoid crowded places.

Take sun protection measures: Consider using physical barriers against the sun whenever possible, such as wearing hats, shirts with sleeves, and avoiding direct sunlight during midday.

Use supplements with caution: Get your nutrition from food sources and do not rely on supplements. Routine intake of nutraceuticals is not recommended for cancer control.

Prevent infection: Maintain good oral hygiene and treat any oral diseases promptly. Pay attention to fresh air in the environment and avoid going to public places or being close to people with upper respiratory tract infections.

Avoid risk factors

Lung cancer patients should avoid exposure to risk factors related to the development of lung cancer.

Strictly quit smoking and stay away from second-hand smoke.

Avoid living or working in an environment full of dust, smoke and chemical irritants.

Avoid or reduce going out in smoggy weather. If you need to go out, you should wear an anti-haze mask.

Disease monitoring

Patients and family members should pay close attention to the symptoms caused by ALK inhibitor-related toxicity, and seek medical treatment promptly if there is any discomfort.

Follow-up and review

Regular review is required after lung cancer treatment. The purpose of review is to monitor the efficacy of treatment and early detection of tumor recurrence and metastasis. The examination is mainly based on imaging tests, such as chest CT, abdominal CT or ultrasound.

Content of review

Since most of the HER2 mutation-positive lung cancer patients belong to the middle and late stages, the specific review plan and items need to strictly follow the doctor’s instructions.

In general, it is recommended to review the disease once every 3 to 6 months, or as prescribed by the doctor.

Review programs may include chest and abdominal CT, bone scan and PET-CT.

Special Reminders

If symptoms such as severe cough, chest pain, hemoptysis, or other discomforts such as progressive fatigue occur during the follow-up period, you should return to the hospital for follow-up.

Prevention

HER2 mutation-positive lung cancer is only one molecular subtype of lung cancer, and lung cancer is the most common lung malignancy, so accurately speaking, the prevention of lung cancer in the general population should be the prevention of all lung malignancies.

Cancer prevention is mainly about reducing the risk of developing cancer. It can be broadly divided into daily prevention and regular screening.

Daily prevention means reducing or avoiding the risk factors of lung cancer and increasing the protective factors of lung cancer.

Regular screening means that the general population should do regular medical checkups, and high-risk groups are recommended to consult a specialized doctor and follow the doctor’s instructions for lung cancer screening.

Causes

The etiology of lung cancer is still not completely clear, and may be related to genetic abnormalities and internal and external environmental cancer-causing factors.

Related pathogenesis

A common consequence of HER2 gene/protein alterations is the over-activation of the receptor following increased homo- or heterodimerization and autophosphorylation, which triggers a variety of signaling pathways leading to uncontrolled cell proliferation.

Lung Cancer Causative Factors

It is currently believed that lung cancer is associated with smoking and passive smoking, occupational exposure, air pollution, radiological factors, genetic factors, and other factors (e.g., tuberculosis, chronic obstructive pulmonary disease, tuberculosis, idiopathic pulmonary fibrosis, scleroderma, etc.).

Symptoms

Symptoms of HER2 mutation-positive lung cancer are not significantly different from those of other types of lung cancer, and it is impossible to determine whether or not it is HER2 mutation-positive lung cancer by symptoms.

Main symptoms

Generally, HER2 mutation-positive lung cancer is usually found in the middle or late stage, so the symptoms mainly show the symptoms of tumor invasion or metastasis, such as pleural effusion, hoarseness, phrenic nerve paralysis, dysphagia, etc. In addition, there may also be symptoms caused by the primary tumor.

There may also be symptoms caused by the primary tumor, such as cough, hemoptysis, dyspnea and so on.

Seek medical treatment

There is no significant difference between the medical consultation for HER2 mutation-positive lung cancer and other types of lung cancer.

Department of Medicine

Medical Oncology

When a diagnosis of HER2 mutation-positive lung cancer is confirmed, it is recommended to seek further professional advice from the Department of Medical Oncology.

Thoracic Surgery

Patients who are suitable for surgery may visit the Department of Thoracic Surgery.

Preparation for medical treatment

Preparation for consultation: registration, preparation of documents, FAQs

Tips for your visit

Patients may need to undergo a chest X-ray or CT examination, so please avoid wearing clothing with metal zippers or buttons, sequins, etc.

Preparation Checklist

Symptom Checklist

Pay particular attention to the time of onset of symptoms, specific manifestations, etc.

Is there any cough or sputum, and how long has it been there?