Breast cancer is one of the most common malignant tumors in women, which seriously threatens women's lives and health. With the continuous development of medical technology, the treatment of breast cancer is constantly updated. As an innovative medical concept, the multidisciplinary integrated treatment (MDT) model brings together the professional wisdom of various disciplines such as surgery, internal medicine, radiotherapy, pathology, and imaging, and through the close cooperation of interdisciplinary expert teams, it has tailored a personalized and all-round treatment plan for patients, thus playing a vital role in improving treatment effect, prolonging patient survival and improving quality of life.
In order to better promote the application of the MDT model in the treatment of breast cancer, China Medical Tribune and the team of Professor Zhang Jin from Tianjin Medical University Cancer Hospital jointly created a column of "Jin" Good Words. This column aims to provide valuable experience and reference for medical workers and patients by sharing high-quality breast cancer MDT cases, and promote the standardization, individualization and precision of breast cancer treatment.
Case Profile
Professor Liang Yan, a doctor from the MDT team of Gansu Provincial Cancer Hospital, reported the medical records as follows.
PART.01 General
Patient Chen, female, 36 years old.
Chief complaint: found right breast mass for 3 months, married and childbearing, not menopause, no family history of malignant tumors.
Specialist examination: a mass of about 3.0×2.0 cm in size can be palpated at 2.0 cm from the nipple at 10 o'clock in the right breast, hard, unclear border, poor mobility, and one enlarged lymph node can be palpated in the right armpit, with a diameter of about 1.5 cm, slightly hard, clear boundary, acceptable range of motion, and the rest (-).
Mammography at a local hospital: right breast hyperdensity, 30×18 mm; BI-RADS: class IVc. The first hospitalization was on December 22, 2021.
PART.02 Diagnosis and treatment history
Admission Diagnosis:
右侧乳腺恶性肿瘤cT2N1M1 IV期，分子分型Luminal B型
First-line treatment:
The patient was a premenopausal patient with newly diagnosed stage IV breast cancer, bone metastases as oligolesions, and was given first-line rescue chemotherapy, TECx6 regimen (nab-paclitaxel + epirubicin + cyclophosphamide), IV, Q3W, zoledronic acid 4 mg, IV, Q4W.
Image Evaluation:
After 6 cycles of rescue chemotherapy, ultrasound imaging was used to evaluate the partial response (PR) of the primary tumor, the lymph nodes to achieve complete response (CR), and the clinical PR was achieved by MRI evaluation.
The patient's mammography was initially taken from an out-of-hospital hospital, and then mammography was performed after 6 cycles of rescue chemotherapy.
After the initial diagnosis of stage IV breast cancer rescue therapy, under the premise of local effectiveness, surgical treatment of the primary lesion was considered, and on May 20, 2022, wide resection of the right breast cancer lesion + local tissue flap metastasis mammoplasty + ipsilateral axillary lymph node dissection was performed.
The postoperative pathology is as follows.
(right breast) invasive ductal carcinoma of the breast, grade II, non-specific type;
cytoplasmic hyaline change of tumor cells, intravascular cancer thrombus (-);
No cancer was seen at the margins (upper, inferior, medial, outer, substralsiological);
There was no cancer metastasis in 0/11 axillary lymph nodes (2 of them had a post-treatment reaction);
免疫组化（ER 3+ 90%，PR 1+ 20%，HER-2 2+，FISH阴性，Ki67 +10%）；
MP Rating: Level 3;
术后分期：ypT1c（1.5×0.7 cm）N0(0/11)M1；
术后分型：Luminal A型。
Professor Yang summarized the medical records:
The patient was treated for stage IV breast cancer before menopause, the primary tumor and axillary lymph nodes were relieved after rescue chemotherapy, the bone metastases were stable, the patient was given local surgery on the breast, and the MP grade was 3 after pathological evaluation, and the rescue endocrine therapy and bisphosphonates were continued to be given, and the follow-up condition was stable, but there were also some problems in the initial treatment of this patient.
For HR+/HER2- young patients with newly diagnosed stage IV breast cancer, the preferred first-line rescue treatment regimen? In particular, the patient only has bone metastases, how to apply a more preferred rescue treatment regimen? For patients with newly diagnosed stage IV breast cancer who respond to rescue therapy, should surgical treatment be considered for the primary lesions?How to choose the surgical method?The extent of local radiotherapy for the primary lesions?How to deal with the local metastases?and the follow-up rescue treatment plan?
These are all treatment problems in the treatment process and subsequent treatment of the patient.
Expert Discussion
Professor Liu Xinlan's team
Meng Shuping, Department of Pathology: The patient's primary tumor, axillary lymph nodes and bone metastases were confirmed by puncture, and the classification of the primary tumor and the classification of metastases were consistent, and the pathological type of bone metastases was clearly diagnosed, which is of great significance for guiding comprehensive treatment.
Zhao Yanjiao, Department of Breast Surgery: The controversy over whether to undergo surgery for newly diagnosed stage IV breast cancer has been a hot issue of great concern around the world in recent years. I believe that the patient was diagnosed with stage IV for the first time, and after effective systemic control, under the premise that the primary disease and metastases of the breast were stable, considering the age of the patient, the breast could be further controlled by palliative surgery. Postoperative treatment is required for further comprehensive treatment to control the disease.
Yan Gang, Department of Radiation Oncology: The patient was diagnosed with stage IV for the first time, and breast cancer bone metastasis is a systemic malignant disease, and the treatment should be mainly systemic therapy. Reasonable local treatment can better control the symptoms related to bone metastasis, and surgery and radiotherapy are effective means for local treatment of bone metastasis.
Professor Liu Xinlan: This patient is a young woman, not postmenopausal, newly diagnosed with stage IV, accompanied by bone metastases, and the pathological indication is HR+/HER2-. Based on the guideline recommendations, patients are initially recommended to undergo targeted therapy with CDK4/6 inhibitors combined with endocrine therapy. However, the efficacy evaluation PR after 6 cycles of rescue chemotherapy in patients with TEC regimen. Subsequently, it was recommended that the patient be switched to CDK4/6 inhibitors in combination with endocrine maintenance therapy. CDK4/6 inhibitors have been shown to significantly improve PFS not only in postmenopausal HR+/HER2- advanced breast cancer, but also in premenopausal HR+/HER2- advanced breast cancer, even in head-to-head studies with chemotherapy, where CDK4/6 inhibitors plus endocrine therapy provide clinically meaningful PFS benefits over chemotherapy. In the Young-PEARL study, palbociclib, a targeted CDK4/6 inhibitor, in combination with endocrine therapy for premenopausal HR+/HER2- advanced breast cancer, also significantly prolonged the PFS phase compared with chemotherapy.
Professor Zhang Jin's team
Radiology: Bone radionuclide imaging (ECT) is the most commonly used method to screen for bone metastases. In addition, imaging evaluation includes X-ray examination, CT, MRI, PET-CT, etc., and the patient's bone metastasis was evaluated by baseline CT after bone scan was confirmed, and the treatment efficacy of breast cancer bone metastasis patients should be evaluated according to the treatment cycle in the process of receiving drugs to judge the effectiveness of treatment. The efficacy evaluation was mainly carried out from multiple aspects such as patient symptoms and imaging examinations. Generally speaking, the reduction of the patient's subjective bone pain symptoms, the clarification of the boundary of the intraosseous lesion, the increase in density, the reduction of the volume of the soft tissue mass, the liquefaction necrosis in the tumor center, and the reduction of tumor uptake by ECT or CT may indicate that the tumor treatment is effective.
Yang Yiling, Department of Breast Pathology: The patient's bone metastases have been pathologically confirmed to be very important for the accurate staging and later treatment of the patient, and the pathological type of breast cancer bone metastasis may be changed. This is because the cell types at the site of primary breast cancer and its bone metastases may not be identical, and the cell types at the site of bone metastases may evolve.
In breast cancer bone metastases, the pathology type may not be exactly the same as that of the primary cancer, for example, a hormone receptor-positive primary cancer may lose hormone receptor expression at the site of bone metastases, while a triple-negative primary cancer may present as a hormone receptor-positive or HER2+ bone metastases. Cell types at the site of bone metastases from breast cancer may also evolve. In the early stages of bone metastasis, breast cancer cells may coexist with bone cells and activate bone resorption, resulting in bone erosive bone metastases. However, after metastasis progression, breast cancer cells may undergo phenotypic transformation, resulting in bone-forming bone metastases. This phenotypic transformation may involve complex interactions and signaling pathway regulation between breast cancer cells and osteocytes. Due to the existence of this change, some breast cancer bone metastases require pathological puncture or biopsy to determine whether pathological changes have occurred, so as to affect the use of treatment or change the treatment plan, and the primary and metastatic lesions of the patient have been pathologically confirmed to have the same molecular typing.
Chen Zhongjie, Department of Radiation Oncology: Radiotherapy is an effective palliative treatment for breast cancer bone metastasis. Its purpose is to prevent or alleviate symptoms and functional impairment caused by bone metastases during the limited survival period of patients, and can also be used for local control of rapidly progressing lesions after palliative surgery. At the same time, with the development of tumor drugs, for patients controlled by systemic drugs, especially patients with oligometastases, local radiotherapy can further consolidate the systemic effect and prolong survival. The regimen of radiation therapy for bone metastases depends on the location of the metastases, the proximity of the limited organs, the degree of pain, and the decision to retreat the total and fractional doses.
Radiation therapy methods include external beam radiation and intraradionuclide irradiation. It is the preferred method of palliative radiotherapy for bone metastases of breast cancer. Local radiation therapy is a rapid and effective way to relieve pain caused by bone destruction and soft tissue lesions, slowing local disease progression. With the development of radiotherapy technology, the emergence of intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) technology has significantly improved the efficiency of radiotherapy compared with ordinary radiotherapy, and at the same time reduced the damage and complications to surrounding tissues. For bone metastases such as the spine and pelvis, stereotactic radiotherapy has become the mainstream treatment technique because of its close proximity to important and complex anatomical structures such as the spinal cord and cauda equina. The patient's breast can be further controlled by radiotherapy after local breast-conserving surgery, and the bone metastasis site can be further improved by local radiotherapy while the systemic treatment is stable.
Liu Jingjing, Breast Surgeon: Pathological biopsy of the patient's primary and metastatic lesions is not only used as the basis for diagnosis, but also under the premise of clear molecular typing, the patient should be treated with precise rescue. In the stage of stable disease control, the local control effect of surgical treatment cannot be ignored. In terms of the choice of breast surgery, breast-conserving surgery and axillary surgery can be used for patients who meet the requirements of breast-conserving surgery to achieve the purpose of local control. At the same time, the patient should continue systemic therapy after surgery to improve the patient's survival.
Prof. Jin Zhang: Systemic systemic therapy is the first choice for patients with newly diagnosed stage IV breast cancer, including chemotherapy, endocrine therapy, targeted therapy, etc. The role of surgery in newly diagnosed stage IV breast cancer has been controversial and there is still no consensus.
The main prospective studies related to this question are: the TATA study, the TBCRC 013 trial, and the MF07-01 study. The first two studies suggest that local surgical treatment of the primary tumor in addition to a remission with first-line chemotherapy does not improve overall survival (OS) in patients with advanced breast cancer. In the MF07-01 study, at 40 months of follow-up, the OS period of patients in the surgical sequential systemic therapy group was significantly longer than that in the systemic therapy alone group, and subgroup analysis showed that for patients with stage IV breast cancer with isolated bone metastases, aged < 55 years and HR+/Her2-, surgical treatment combined with systemic therapy could prolong the survival by 14 months. From the results of the MF07-01 study, it can be seen that local surgical treatment can reduce tumor burden, and may also reduce the number of drug-resistant tumor cells, which in turn has a positive effect on subsequent systemic therapy. At this time, there is a "time window" problem in surgical treatment, that is, if the residual tumor of the primary lesion is not resected by surgical intervention as soon as possible, the residual tumor tissue of the primary lesion may still differentiate and form a new metastasis, which will affect the efficacy of subsequent systemic therapy and ultimately affect the survival of the patient. In this case of premenopausal hormone receptor-positive advanced simple bone metastases, and the patient is less than 40 years old, surgery should be performed on the basis of effective systemic therapy. Surgery is also a type of local treatment, which is part of the rescue treatment, and the local breast-conserving surgery can be performed under the premise of breast-conserving surgery.
In addition, based on guidelines and evidence-based medical evidence, OFS combined with CDK4/6 inhibitors combined with AI therapy is recommended to achieve a better "net benefit", under the framework of "net benefit", the goal of breast cancer treatment is not only to improve the efficacy, but also to reduce the toxic side effects of treatment, maximize the survival time, and improve the quality of life and long-term health and function of patients.
Professor Wang Yongsheng's team
Xu Min, Department of Radiation Oncology: The patient is currently under stable control in the follow-up stage, and radiotherapy is an important treatment method for the treatment of bone metastasis accompanied by breast cancer, especially when accompanied by local pain symptoms, the local tumor compression can be quickly reduced through radiotherapy, so that the pain can be relieved, and the patient's quality of life can be rapidly improved. It should be noted that while radiotherapy is carried out for patients with breast cancer bone metastasis, systemic treatment cannot be neglected, and the combination of systemic treatment and local treatment can effectively improve the condition of breast cancer bone metastasis patients and prolong the survival time of patients.
Lihua Song, Department of Medical Oncology: With the launch of CDK4/6 inhibitors, the treatment landscape of HR+/HER2 advanced breast cancer has changed. Clinical studies and real-world studies have confirmed that the CDK4/6 inhibitor palbociclib combined with endocrine efficacy is definite, and the adverse reactions are tolerable, and the patient has HR+/HER2-IV breast cancer, which has been systematically evaluated as oligometastases, and the initial CDK4/6 inhibitor combined with endocrine therapy is recommended. Given the availability of medicines and evidence-based medical evidence at the time, palbociclib was more effective in patients with isolated bone metastases. The patient has been treated with rescue chemotherapy and should be treated with a CDK4/6 inhibitor after surgery.
Xu Liang, Department of Imaging: The most common sites of bone metastasis of breast cancer are the spine, ribs, pelvis and long bones, such as the femur and upper arm bones. According to studies, about 60 to 75 percent of breast cancer bone metastases occur in the spine and pelvis, 20 to 30 percent of bone metastases occur in the ribs and femur, and the rest occur in other sites. The patient had vertebral metastasis, and baseline imaging was clear for the diagnosis of bone metastasis. In the later stages of treatment, imaging evaluation should be performed for three to six months, and care should be taken to avoid strenuous exercise as a weight-bearing bone to prevent pathologic fractures.
Prof. Yongsheng Wang: The most common subtype in patients with bone metastasis is HR+/HER2- breast cancer, and the main goals of comprehensive treatment of breast cancer bone metastasis are to control tumor progression, prevent and treat bone-related events (SREs), relieve pain, restore function, improve quality of life and prolong life. Patients with bone metastasis should be treated mainly with systemic therapy, bone modifiers (such as bisphosphonates, denosumab) can prevent and treat SREs, and should be used as the basic drug for the treatment of bone metastasis in breast cancer.
For the first-line treatment of patients with HR+ advanced breast cancer without endocrine therapy, CDK4/6 inhibitor + AI is the best choice. For patients with bone metastases only, palbociclib combined with AI was associated with a significant benefit in the first-line treatment, with a PFS of 36.2 months and a 59% reduction in the risk of disease progression. It is worth mentioning that approximately 43% of the patients in the PALOMA-2 study were not treated with endocrine therapy, which is consistent with this patient's situation. Therefore, for this patient, palbociclib + AI is the first choice among many CDK4/6 inhibitors in terms of drug availability and evidence-based medical evidence at that time, and this case is a very young patient, and it is particularly important to be able to return to society and normal life after treatment.
Summary of case lessons
Combined with cases and expert discussions, valuable diagnosis and treatment experience is extracted to provide reference and enlightenment for the clinical practice of breast cancer.
The advent of CDK4/6 inhibitors has greatly changed the survival outcome of patients with HR+/HER2- advanced breast cancer, and has become the preferred treatment for HR+/HER2- advanced breast cancer. At present, there is a lack of clinical study data for head-to-head comparison of different CDK4/6 inhibitors, and we can screen the optimal and suitable population of CDK4/6 inhibitors according to the enrollment conditions of the corresponding clinical studies of different drugs based on the support of evidence-based medical evidence.
After rescue surgery and regional radiotherapy, it is a reasonable choice to combine targeted CDK4/6 inhibitor maintenance therapy on the basis of endocrine therapy, which will help to further improve the efficacy, improve the quality of life of patients, prolong the PFS phase and even OS phase, and achieve stable disease and good tolerance to treatment at the last follow-up.
From this example, it is not difficult to see that even after first-line chemotherapy control in patients with HR+/HER2- advanced breast cancer, endocrine drugs combined with CDK4/6 inhibitors can still achieve further improvement in efficacy and survival. In addition, as CDK4/6 inhibitors have rewritten the treatment pattern of HR+/HER2- breast cancer, especially for patients with visceral metastasis and ET drug resistance, ET combined with CDK4/6 inhibitors can also significantly improve their prognosis, and has become the first-line standard treatment regimen unanimously recommended by domestic and foreign guidelines.
In addition, with the successive implementation of medical insurance policies, it is believed that this endocrine treatment regimen will benefit breast cancer patients to a greater extent, and endocrine maintenance therapy will also have more survival advantages. As a result, domestic clinical practice will also change.
The column leads the experts