Breast cancer is the most common tumor among women. Its incidence has steadily increased in recent years, but mortality rates have declined, attributed to early diagnosis of breast cancer and improvements in surgical techniques and radiotherapy.
In addition, new targeted drug therapies have significantly improved the survival of breast cancer patients. Despite significant advances in treatment technology, breast cancer remains the second leading cause of oncologic death in women. This article reviews the latest therapeutic advances in breast cancer, focusing on how to individualize treatment according to the patient’s tumor biology and molecular subtype in the era of targeted breast cancer therapy.
Early stage breast cancer
1. Diagnosis
The diagnostic guidelines for early-stage breast cancer have not changed much so far. The NHS Breast Screening Programme in the UK recommends that people between the ages of 47 and 73 should be routinely screened with mammography. Both men and women should visit their local breast specialist as soon as possible (usually two weeks) to avoid any delay in treatment, and mammograms, breast ultrasounds and biopsies should be completed as needed.
2.Local treatment
Surgical treatment must be thorough. Breast-conserving surgery followed by radiotherapy and total mastectomy have basically the same survival period. For surgical treatment of breast cancer, the excision range should be at least 1mm from the edge of the lump and should have good cosmetic effect. Mastectomy is recommended in the following cases: if the size of the lump is not suitable for breast-conserving surgery, if the lump is a multifocal lesion, if the size of the lump is so large that even if breast-conserving surgery is performed, the cosmetic result cannot be achieved, or if the patient so requests. Preoperative adjuvant therapy to reduce the size of the lump is increasingly recommended, and this method can increase the chances of breast-conserving surgery.
3.Lymph node dissection in the axilla
While diagnosing breast cancer, ultrasound examination or biopsy of suspected lymph nodes in the ipsilateral axilla should be performed to determine the stage of breast cancer. If the axillary lymph nodes are negative, sentinel lymph node biopsy (SLNB) is performed, which is usually done at the same time as breast surgery. Previously, in patients with positive sentinel lymph nodes, a total axillary lymph node dissection (ALND) was also performed. The main objective of performing ALND is to reduce axillary recurrence. In fact, in 50% of patients with positive sentinel lymph nodes, no other axillary lymph node invasion was found after ALND. Should patients with positive sentinel lymph nodes undergo further ALND?The Z0011 clinical study answered this question.
The study was a phase 3 randomized controlled study that included over 800 patients with breast cancer. 891 patients were randomized to either the SLNB only group (446) or the further ALND group (445). All patients received segmental mastectomy and breast radiotherapy, with systemic adjuvant therapy as indicated. At a median follow-up of 6.3 years, the 5-year breast recurrence rates were 3.7% and 2.1% in the ALND and SLNB groups, respectively, and the 5-year lymph node recurrence rates were 0.6% and 1.3%, respectively.
The results of the Z0011 trial showed that there was no significant difference in overall survival, disease-free survival, and local recurrence rates between patients with and without axillary lymph node dissection for breast cancer with positive anterior lymph node metastases, i.e., in these respects, patients with breast cancer with positive anterior lymph nodes did not benefit from further axillary lymph node dissection.
To date, there is no international consensus on whether patients with positive sentinel lymph nodes in breast cancer should undergo further ALND. Recent guidelines suggest that for patients undergoing breast-conserving surgery after radiotherapy, further ALND may not be necessary if one or two of the sentinel lymph nodes are positive.
4. Adjuvant therapy based on the pathology and molecular subtype of breast cancer
In estrogen receptor-positive patients with poor conventional staging, there is heterogeneity in their molecular subtypes, and their sensitivity to chemotherapy and responsiveness to endocrine therapy are not the same. The prognosis of poorer staging due to high T-staging and positive lymph nodes may be influenced by some good molecular biological features, such as hormone receptor positivity, low Ki-67 expression, and low risk for gene 21.
When there is inconsistency in staging and staging, single gene and multigene profiling tests may give us more information, but the advantage of multigene testing is currently mainly in the prediction of prognosis, and the prediction of treatment outcome is yet to be further confirmed.
Standard chemotherapy should be avoided in patients with poorly staged pathology who have good hormone responsiveness, Her2 negativity, and low proliferation (low risk for 21 or 70 gene expression). It is most important to distinguish between patients who are estrogen receptor positive and those who are negative, as the treatment and prognosis of these two groups of patients are very different.
Adjuvant chemotherapy for early stage breast cancer
1. Hormone therapy for the first 5 years
The aim of adjuvant therapy is to improve the chance of cure by eliminating micrometastatic lesions. About 80% of breast cancer patients are estrogen receptor positive. For these patients, adjuvant tamoxifen treatment for five years can reduce the recurrence rate by 41% and the mortality rate by 31%. For pre-menopausal breast cancer patients, tamoxifen remains the standard of care.
For post-menopausal breast cancer patients, studies have demonstrated the superiority of aromatase inhibitors over tamoxifen. Data from two large studies, ATAC and BIG1-98, showed that anastrozole and letrozole were more effective than tamoxifen.
It is important to monitor bone mineral density in patients treated with aromatase inhibitors; if osteoporosis develops, calcium and vitamin D supplements should be added, as well as bisphosphonates and Prolia (denosumab) if necessary. For patients with premenopausal diagnosis of breast cancer, postmenopausal (physiological or chemotherapeutic effect) use of aromatase inhibitors remains beneficial.
2. Hormonal adjuvant therapy after 5 years
Patients with estrogen receptor-positive breast cancer tend to recur after 5 years. For menopausal patients who have been treated with tamoxifen for 5 years, treatment with letrozole, a non-aromatase inhibitor, can reduce the relative risk by 42%. For patients who have been treated with tamoxifen for 5 years and are not menopausal, or who cannot tolerate aromatase inhibitors, continued use of tamoxifen may benefit the patient.
Results from the International ATLAS (comparing long-term versus short-term adjuvant tamoxifen therapy) study showed that 10 years of tamoxifen reduced late recurrence and mortality rates in patients with ER+ breast cancer better than 5 years of standard tamoxifen therapy. The most significant additional benefit of continuing tamoxifen was a reduction in mortality in the second decade after breast cancer diagnosis.
The ATTom study yielded the same results. Combining the results of the ATLAS study and the ATTom study, extending adjuvant tamoxifen therapy to 10 years instead of 5 years for estrogen receptor-positive breast cancer further reduces the risk of recurrence. Compared to no tamoxifen, 10 years of adjuvant treatment with it reduces the risk of death by at least one-third.
3. Chemotherapy
Chemotherapy can reduce the relative risk of death from breast cancer by one-third, but it does not improve patient survival because there are many patients who can be cured by surgery and hormone therapy alone. Further research is needed to determine which type of patients need chemotherapy. We know that the prognosis of patients can be predicted by molecular tests, such as Oncotype DX. In fact, such tests can also identify patients who can be cured with surgery and hormonal therapy.
The MINDACT study evaluated the clinical value of adding gene expression profiling to conventional clinicopathological testing to guide adjuvant therapy selection in breast cancer patients. It was designed to spare more patients from adjuvant chemotherapy and achieve a better quality of life.
This study is the first attempt to use genetically guided patient classification to reduce the cost of oncology treatment, which not only reflects the concept of giving the right treatment to the right patients, but more importantly, emphasizes that unnecessary treatment should not be given to unsuitable patients.
Of course, in the future, we need to identify high-risk patients for better and more adequate treatment and further explore how to incorporate better tumor subgroup classification as well as biological markers predicting efficacy into adjuvant treatment of breast cancer. Even when chemotherapy is required for breast cancer patients, there is a lot to learn about chemotherapy planning. How to develop a chemotherapy plan to reduce patient mortality and chemotherapy-induced side effects is a current issue to be considered.
4.HER2-targeted therapy
The treatment of breast cancer has entered the era of molecular typing, human epidermal growth factor receptor 2 (HER2) positive breast cancer accounts for about 20-30% of all breast cancer patients, HER2 is a clear prognostic indicator of breast cancer.
The introduction of trastuzumab, the first humanized monoclonal antibody targeting HER2, has changed the prognosis of HER2-positive breast cancer patients. All clinical studies on adjuvant therapy after breast cancer surgery suggest that surgery plus the anti-HER2 treatment drug trastuzumab improves the DFS rate of patients compared to surgery alone, and most clinical trials have also shown improved OS rates.
For patients with large masses that are not suitable for breast-conserving surgery, preoperative adjuvant chemotherapy, HER2-targeted therapy or hormonal therapy can reduce the tumor load and create the conditions for breast-conserving surgery. For those patients with complete pathological remission, especially those with estrogen receptor negative breast cancer, the prognosis is better.
Patients with locally advanced breast cancer are best treated with adjuvant chemotherapy before undergoing radical mastectomy. For patients with inflammatory breast cancer with symptoms of erythema and edema, the best treatment is preoperative adjuvant chemotherapy, followed by surgery or radiation therapy as appropriate. This is because these patients are unlikely to be hormone receptor positive and more likely to be HER2 gene positive.
Treatment of advanced breast cancer
The main purpose of choosing chemotherapy for advanced breast cancer is to reduce patients’ symptoms, control disease progression and improve survival. In the selection of chemotherapy regimen, attention should also be paid to the toxic side effects caused by chemotherapy to minimize the toxicity of treatment. Depending on the subtype, the median survival after distant metastasis of breast cancer varies, generally ranging from six months to 2.2 years. The overall survival of breast cancer patients has improved significantly over the past 30 years, especially for HER2-positive breast cancers. Metastatic breast cancer is still incurable, but treatment can be used to improve patient survival and quality of life.
1.Hormone therapy
For estrogen receptor-positive metastatic breast cancer, hormone therapy is still the first choice. The choice of hormone therapy regimen should be based on the patient’s previous response to treatment and whether she is menopausal or not. Drug resistance is common and unavoidable in hormone therapy for metastatic breast cancer. How to avoid the problem of drug resistance is a hot topic of current research. mTOR-mediated signaling pathway is highly activated in breast cancer with high frequency, leading to resistance to hormone therapy and becoming an important target for breast cancer treatment.
The results of a study showed that the combination of the mTOR inhibitor everolimus with exemestane in patients with advanced breast cancer prolonged the disease-free progression period and significantly reduced the risk of cancer progression by 57% compared to exemestane alone.
Everolimus can produce serious side effects, including: stomatitis, rash, diarrhea and malaise, and pneumonia is also common. These side effects should be noted during the course of treatment and treated early if they occur. Everolimus has been approved in North America and Europe for the treatment of hormone receptor positive, HER2-positive breast cancer patients.
2.Chemotherapy
Chemotherapy is commonly used for the following types of breast cancer: hormone therapy-resistant breast cancer, hormone receptor-negative breast cancer, rapidly progressive breast cancer, and most HER2-positive breast cancers. The choice of chemotherapy regimen should be tailored to the patient’s physical condition and the nature of the tumor (e.g., triple-negative breast cancer, HER2-positive) as well as previous response to chemotherapy. Chemotherapy is usually a short course of treatment, completed for several cycles. There is no uniform conclusion as to how many courses of chemotherapy are needed.
3.HER2 targeted therapy
Before targeted drugs came out, HER2-positive breast cancer patients were considered to be the category with poor prognosis. With the emergence of humanized monoclonal antibodies targeting HER2, the prognosis of this group of patients has improved significantly. Trastuzumab in combination with paclitaxel significantly improves patient survival in neoadjuvant therapy for HER2-positive breast cancer. Patients with HER2-positive breast cancer who have failed trastuzumab therapy may choose lapatinib, a small molecule kinase inhibitor. Lapatinib is currently approved for second-line use in combination with capecitabine for the treatment of HER2-positive breast cancer.
Trastuzumab emtansine (T-DM1) is an antibody-drug coupled drug for the treatment of HER2-positive breast cancer. the EMILIA study showed that the experimental new drug T-DM1 was better tolerated compared to the capecitabine/lapatinib (XL) combination in 978 patients with HER2-positive metastatic breast cancer, and significantly prolonged progression-free survival and overall survival. As a result of these new agents, the median survival of HER2-positive metastatic breast cancer patients has significantly improved over the past 3 years.
Management of bone metastases from breast cancer
Bone metastases occur in 60-80% of advanced breast cancers. Bone related events include: bone pain, fractures, and spinal cord compression. Zoledronic acid has been shown in previous studies to reduce the risk of complications from breast cancer bone metastases, based on the fact that zoledronic acid inhibits osteoclast-mediated bone resorption.
Denosumab (XGEVA) is a subcutaneously injected monoclonal antibody to XGEVA that binds to RANKL, a membrane-penetrating or soluble protein that is essential for osteoclast formation, function and survival. In solid tumors with bone metastases, osteoclast activity is stimulated by RANKL, and XGEVA prevents RANKL activation, preventing bone marrow-associated events by this principle.
In a recent randomized controlled study, XGEVA was shown to be more effective in reducing bone marrow-related events compared to zoledronic acid. both XGEVA and zoledronic acid can cause hypocalcemia and care should be taken to supplement calcium and vitamin D. The incidence of osteonecrosis of the jaw in patients treated with XGEVA and zoledronic acid was 0.5%-1%. Therefore, while taking these drugs, care should be taken to maintain oral hygiene and avoid dental-related procedures as much as possible.
Management of brain metastases from advanced breast cancer
The incidence of brain metastasis in HER-2 positive breast cancer is higher than that in HER-2 negative breast cancer because most chemotherapeutic agents, such as trastuzumab, do not cross the blood-brain barrier.
The presence of brain metastases in breast cancer patients is mostly indicative of a poor prognosis. For patients with multiple brain metastases, whole brain radiotherapy is the standard of care, and for patients with solitary brain metastases or oligometastatic disease, tumor reduction surgery or stereotactic radiotherapy may be considered. Some patients with brain metastases from breast cancer can also achieve excellent results after treatment.
Outlook
At the genetic level, breast cancer is a highly heterogeneous disease. For HER2-positive breast cancer patients, the introduction of trastuzumab has given hope to this breast cancer with poor prognosis. The future era of breast cancer treatment will be the era of molecular targeted therapy. In the past decades, the treatment of breast cancer has changed from traditional radical breast cancer surgery and radiotherapy to multimodal individualized treatment. With the continuous progress of medical treatment, it is believed that the survival and quality of life of breast cancer patients will be greatly improved.