"Rare + rare" BRAF V600 mutation + lung adenocarcinoma breast metastasis, D+T treatment success case sharing

*For medical professionals only

Dabrafenib + trametinib was effective in the third-line treatment of lung adenocarcinoma breast metastasis, and PFS continued for 7 months in 5-year lung cancer patients

In recent years, clinical research on non-small cell lung cancer (NSCLC) has developed rapidly, and in terms of targeted therapy, from the familiar targets such as EGFR, ALK, ROS1, and RET to the newer BRAF V600, rare and refractory lung cancer targets have been explored and drugs have been continuously developed, and the diagnosis and treatment of NSCLC has gradually entered an era of precision and standardization.

BRAF, as a relatively rare NSCLC driver gene, is common in patients with lung adenocarcinoma, with a BRAF mutation rate of about 2%~4%[1], with V600E mutation being the most common, accounting for about 50%[2]. In the past, there was no corresponding targeted drug for BRAF-mutant NSCLC, and chemotherapy was mainly used in clinical practice, but the efficacy was not ideal, and the survival time of patients rarely exceeded 1 year, and the survival prognosis was extremely unoptimistic. Now, with the approval of dabrafenib + trametinib (D+T for short) in foreign and domestic countries for the treatment of BRAF V600-positive NSCLC, the concept of "precision therapy" has officially announced that the concept of "precision therapy" has come to this subtype field, and the combination therapy regimen of D+T can significantly prolong the progression-free survival (PFS) of patients compared with traditional chemotherapy, and has shown amazing efficacy in clinical practice, which is a boon for patients.

This issue of "Less-Target Practical Practice" will share the diagnosis and treatment experience of a patient with stage IV BRAF V600-positive adenocarcinoma of the right lung, who has been diagnosed with lung adenocarcinoma for more than 5 years before the visit, and has achieved PFS benefits of 20 and 39 months respectively after the previous first-line and second-line treatment, this time due to disease progression (PD), combined with multiple metastases, the patient's general condition is poor (ECOG score = 2 points), intolerance to third-line chemotherapy, and after switching to D+T therapy, the imaging and tumor marker indicators have greatly improved. The patient felt well, improved overall, and achieved an additional 7-month progression-free survival (PFS). The case was provided by Professor Wang Shuo from the First Affiliated Hospital of China Medical University, and Professor Jin Bo from the First Affiliated Hospital of China Medical University was invited to comment.

Case Profile

➤ Basic information

Basic information: Female, 61 years old

Date of initial consultation: June 2021

Initial complaints: chest tightness, cough, sputum production for 1 month, with dull pain and erythema in the right breast

History of present illness: The patient presented with "chest tightness, cough, white frothy sputum cough with no obvious cause 1 month ago, and felt redness, swelling and pain in the right breast".

• Diagnosis: In March 2016, the patient had paroxysmal dry cough with asthma, and the out-of-hospital examination showed pleural effusion. In April 2016, thoracentesis drainage was performed in the hospital to drain 5000ml of yellow pleural effusion, and cytology showed "lung adenocarcinoma", and on April 29, 2016, pleural puncture pathology showed "metastatic lung adenocarcinoma", immunohistochemistry: CK5/6(-), CK7(+), Napsin-A(+), P63(-), CK(+), Vimentin(-), WT1(-), PAX8(-), TTF-1(+), CD56(-), Ki-67 (about 5%+), genetic testing of EGFR exons 18, 19, 20, and 21 showed no abnormalities.

• First-line treatment: On May 25, 2016, the patient started gemcitabine + platinum drugs (GP regimen) chemotherapy for 6 cycles, and the evaluation was stable (SD). On November 24, 2016, the patient was started on single-agent gemcitabine (G) maintenance chemotherapy for 7 cycles, and the last chemotherapy was in May 2017. On February 1, 2018, the patient was found to have a loculated effusion at the right apical lung, and the fluid was drained and cytology was performed to find suspicious malignant cells, and the disease recurrence was considered. Progression-free survival (PFS) at this stage is 20 months.

• Second-line treatment: In February 2018, the patient started pemetrexed + platinum (PP regimen) chemotherapy for 5 cycles, and after 2 and 4 cycles of chemotherapy, the evaluation was partial response (PR), followed by single-agent pemetrexed maintenance chemotherapy for 10 cycles, and the last chemotherapy was on March 20, 2019, and the PFS in this stage has lasted for 39 months.

Anamnesis: hypertension for 13 years, well controlled by irbesartan, diabetes mellitus for 13 years, blood sugar control at about 10mmol/L

Personal history: Denial of smoking, alcohol history

Family history: Father with lung cancer, deceased

➤ Relevant examinations

• Symptoms and physical examination: the patient has obvious dyspnea, worsening after exertion, frequent coughing, swelling and pain of breast masses, swelling of both lower limbs and right upper limbs, and irregular erythematous changes on the surface of the right breast and around the right axilla

• Double breast ultrasound showed that the right breast parenchymal space-occupying lesion was not excluded, and nipple invasion was not excluded, accompanied by edema-like changes in the skin and subcutaneous fat layer (class BIRADS4B-4C), combined with magnetic resonance examination of right axillary lymphadenopathy (grade 4), and severe hyperplasia of both breasts

Figure 1. Double breast ultrasound

• On May 28, 2021, the pathology of ligonode puncture of the right breast and right axillary lymph node showed that:

(A right breast): adenocarcinoma, immunohistochemistry results suggest that lung adenocarcinoma has a high possibility of metastasis

免疫组化：MLH1（+），MSH2（+），MSH6（+），PMS2（+）

(B right axillary lymph node): lymph node metastasis, immunohistochemistry results suggest that lung adenocarcinoma has a high possibility of metastasis

免疫组化：Calponin（-），ER（-），C-erbB-2（1+），CK5/6（-），E-cadherin（+），Ki-67（30%），P120（+），PR（-），P63（-），GATA-3（-），Napsin-A（+），TTF-1（+），SPB（+）

• （乳腺穿刺）基因检测：BRAF V600E突变，PD-L1（TPS=20%）

Figure 2. Breast puncture pathology (left), genetic test report (right)

• CT of the lungs: mass of the lower lobe of the right lung, multiple interstitial inflammatory changes in both lungs, except for carcinomatous lymphangitis; Multiple metastatic nodules in both lungs and right pleura, right pleural effusion, pericardial effusion, and enlarged mediastinal lymph nodes; Radiographic image of the right mammary and swollen lymph nodes in the right axilla

Figure 3. CT of the lungs

Clinical diagnosis:1. Adenocarcinoma of the right lung, stage IV, with lymph node metastases in both lungs, right pleura, right breast, and right axillary (BRAF V600E positive, ECOG score=2 points)2. Pericardial and pleural effusion 3. Hypertension 4.Diabetes mellitus 5.Hypoxemia

Treatment

■ 1. Phase I: 1 cycle of chemotherapy, poorly tolerated and abandoned

On July 8, 2021, the patient refused targeted therapy for financial reasons and requested chemotherapy. Considering that the patient's previous use of pemetrexed was effective, and considering the patient's current physical status, pemetrexed monotherapy was performed for 1 cycle, and the patient felt chest tightness and shortness of breath worse than before after chemotherapy. Pleural effusion and pericardial effusion were found on examination, and after thoracentesis catheterization and drainage of 800ml pleural effusion and anti-inflammatory symptomatic treatment, the symptoms of shortness of breath improved, and the pericardial effusion was not treated.

On July 30, 2021, the patient's re-examination of lung CT showed that after 1 cycle of chemotherapy, the lesion was stable, but the pleural effusion and pericardial effusion increased compared with before, and the patient's general condition was poor and he was poor in tolerance to chemotherapy.

■ 2. Phase II: Challenge D+T dual-target therapy to fully take effect, and obtain PFS for more than 7 months

On August 2, 2021, the patient started dual-target treatment with dabrafenib + trametinib, and after 2 weeks, the patient's symptoms of shortness of breath and lower limb edema improved compared with before, and 1 month later, imaging showed that the patient's pulmonary metastases were reduced compared with before, axillary lymph nodes and breast metastases were reduced, and the irregular erythema changes on the surface of the right breast and around the right axillary skin were reduced, the color and range were reduced compared with before, and the pain was relieved. The tumor markers carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA125), carbohydrate antigen 153 (CA153) and carbohydrate antigen 199 (CA199) were also rechecked during the medication period, and all indicators were reduced, and the first three indexes had decreased to normal values. The patient was treated with targeted therapy until March 2022, PFS time was more than 7 months, fever occurred at the beginning of taking the drug, improved after symptomatic treatment, continued to take the drug, no other obvious adverse reactions, and the best efficacy achieved partial remission.

Figure 4. Chest CT changes before and after 1 and 6 months of dual-target therapy (from top to bottom)

Table 1. Tumor marker index change table (top left: CEA, bottom left: CA125, top right: CA199, bottom right: CA153)

Expert commentary

■ Prof. Jin Bo: The D+T regimen combines the advantages of efficacy, safety and accessibility, and is the preferred regimen for patients with BRAF V600 mutant NSCLC

Lung adenocarcinoma is a common type of lung cancer that is prone to recurrence or distant metastasis, and the common metastasis sites are bone, lung, brain, adrenal glands, liver, and lymph nodes [3]. Rib metastasis is also common, while metastasis to the breast is rare and is an advanced manifestation, accounting for only 0.5%~2% of primary cancer metastasis [4]. Patients with metastatic breast tumors have an overall poor prognosis, with a median survival (OS) of 10 to 15 months, with the shortest being less than one month [5-6]. Breast metastasis of lung cancer is usually the direct invasion of lung veins by cancer cells, and then metastasis to breast tissue through hematogenous metastases to form intramammary metastases, and its treatment strategy is mainly anti-tumor therapy for primary tumors (lung cancer), which requires comprehensive consideration of various factors such as the patient's driver gene status, pathological type, and constitution, and carries out systemic comprehensive treatment, which is completely different from the treatment of primary breast cancer [7], so differential diagnosis is very important.

For example, TTF1 and NapsinA are strong biomarkers for lung adenocarcinoma, while GATA3 is a sensitive marker for primary breast cancer [8]. There is no single marker with 100% sensitivity and specificity for the identification of metastatic breast lesions, so it is necessary to use a group of antibodies to detect and analyze clinicopathological features at the same time. In view of his history of lung cancer, coupled with further pathological and other examinations, it was also determined that his breast lesion was metastasized, and the genetic test showed BRAF V600E mutation.

Previous clinical research data have shown that the efficacy of single-target therapy in patients with BRAF V600E mutation is limited, and the D+T dual-target treatment mode can achieve better efficacy. The BRAF gene encodes serine/threonine protein kinase, which is involved in the activation of the RAS-RAF-MAPK signaling pathway downstream of the epidermal growth factor receptor (EGFR), and is involved in a series of biological activities such as cell growth, differentiation and apoptosis. Mutations in the BRAF gene continue to activate the mitogen-activated protein kinase pathway (MAPKs), which can lead to uncontrolled cell proliferation and differentiation, and are thought to be a key factor in tumor development [9-10]. Dabrafenib is a selective inhibitor of BRAF kinase activity, and trametinib is a reversible, highly selective allosteric inhibitor of MEK1 and MEK2 kinase activity, and the combination of the two can inhibit both BRAF and MEK targets, block BRAF and MEK from upstream and downstream simultaneously, and comprehensively inhibit the formation of MAPK upper and lower pathways, resulting in rapid and significant remission of lesions [11-12].

Multiple real-world evidence (RWE) [13-16] adds strong evidence for the use of D+T in the treatment of BRAF V600 NSCLC, particularly in the first-line standard of care setting. The efficacy of D+T has also been demonstrated in this patient, who chose chemotherapy for third-line treatment for economic reasons, and switched to targeted therapy after one cycle due to poor tolerance to chemotherapy. After the patient started D+T dual-target therapy, all tumor markers were reduced to normal after reexamination, and the imaging showed that the patient's pulmonary metastases were reduced, axillary lymph nodes and breast metastases were improved, the edema of the lower limbs was reduced compared with before, the patient's general state, shortness of breath and other symptoms were significantly improved, and the color of the skin erythema on the breast surface changed and faded. The overall safety profile of D+T is favorable, and dual-target therapy does not increase the incidence of adverse effects with the addition of one drug [17-18]. It has been more than 7 months since the targeted therapy of the patient, and there are no obvious adverse reactions, and the excellent efficacy is still continuing.

In March 2022, the D+T dual-target treatment regimen was approved for lung cancer indications in China, and in less than a year, it was successfully included in the new round of medical insurance reimbursement, and the price was significantly reduced, which greatly improved the accessibility of D+T drugs.

Review Expert Profile

Prof. Bo Jin

• Professor, Deputy Director, Department of Medical Oncology, The First Affiliated Hospital of China Medical University
• Member of the Standing Committee of the Oncology Branch of the Chinese Geriatrics Society
• Member of the Standing Committee of the Chemotherapy Committee of the Chinese Anti-Cancer Association
• He is a member of the Special Committee on Molecular Targeted Therapy for Tumors of the Chinese Society of Biomedical Engineering
• Member of the Standing Committee of the Tumor Immunotherapy Committee of the Chinese Medical Education Association
• Member of the Standing Committee of the Difficult Oncology Committee of the Chinese Medical Education Association
• Member of the Standing Committee of CSCO Cardiology Committee
• Member of CSCO Nervous System Oncology Committee
• Member of CSCO Vascular Targeting Committee
• Vice Chairman of the Lung Cancer Committee of the Beijing Cancer Research Association
• Vice Chairman of the Immunization Committee of the Beijing Cancer Prevention and Treatment Research Association
• Member of the Standing Committee of the Lung Cancer Youth Committee of the Beijing Medical Award Foundation

Specialist profiles are provided with cases

Prof. Shuo Wang

• Associate Professor, Department of Medical Oncology, First Hospital of China Medical University, Doctor of Oncology
• Youth member of the Tumor Marker Committee of the Chinese Anti-Cancer Association
• He is a young member of the Lung Oncology Professional Committee of the Chinese Medical Education Association
• Member of the Medical Technology Professional Committee of the Chinese Hospital Association
• He is a member of the 1st Tumor Hyperthermia Professional Committee of the Chinese Anti-Cancer Association
• Member of the Gastric Cancer Prevention and Control Committee of the Beijing Cancer Prevention and Control Society
• Member of the Cancer Rehabilitation Committee of the Chinese Society of Gerontology and Geriatrics

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