Breast cancer remains 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 cancer death in women. An
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
Diagnosis
Guidelines for the diagnosis of early stage breast cancer have not changed much so far. The NHS Breast Screening Programme recommends routine screening mammography for people between the ages of 47 and 73.
Both men and women should visit their local breast specialist as soon as possible (usually two weeks) to avoid delaying treatment and, if necessary, to have mammograms, breast ultrasounds and biopsies.
Local treatment
Surgical treatment must be thorough. If radiotherapy is followed by breast-conserving surgery and total mastectomy, the patient’s survival is basically the same. For surgical treatment of breast cancer, the extent of excision should be at least 1mm from the edge of the lump and should have a good cosmetic effect.
Mastectomy is recommended in the following cases: the size of the lump is not suitable for breast-conserving surgery, multifocal lesions in the breast, the size of the lump is too large to achieve a good cosmetic result even if breast-conserving surgery is performed, and the patient’s request. Preoperative adjuvant therapy to reduce the size of the lump is increasingly recommended, and this method increases the chances of breast-conserving surgery.
Axillary lymph node dissection
Along with the diagnosis of breast cancer, an ultrasound examination of the ipsilateral axillary lymph nodes or a biopsy of the suspected lymph nodes should be performed to determine the stage of the breast cancer. If the axillary lymph nodes are negative, a sentinel lymph node biopsy (SLNB), which is usually performed at the same time as breast surgery, is performed.
Previously, in patients with positive sentinel lymph nodes, total axillary lymph node dissection (ALND) was also performed. The primary goal of ALND is to reduce axillary recurrence. In fact, in 50% of patients with positive sentinel lymph nodes, no other axillary lymph node invasion is found after ALND. The Z0011 clinical study answered this question as to whether patients with positive sentinel lymph nodes should undergo further ALND.
The study was a phase 3 randomized controlled study with over 800 breast cancer patients. 891 patients were randomized to either the SLNB only group (446) or the further ALND group (445). All patients underwent 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, or local recurrence rates between patients with and without axillary lymph node dissection for breast cancer with positive anterior lymph node metastases, i.e., patients with positive anterior lymph node breast cancer did not benefit from further axillary lymph node dissection in these respects.
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 sentinel lymph nodes are positive.
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 molecular staging and sensitivity to chemotherapy and responsiveness to endocrine therapy. The prognosis of poorer staging due to high T-staging and positive lymph nodes may be influenced by a number of good molecular biological features, such as hormone receptor positivity, low Ki-67 expression, and low risk for 21 genes.
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 gene 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.
Three major molecular subtypes of breast cancer
Adjuvant chemotherapy for early stage breast cancer
Hormonal therapy for the first 5 years
The goal of adjuvant therapy is to improve the chances of cure by eliminating micrometastases. For the approximately 80% of breast cancer patients who are estrogen receptor positive, adjuvant tamoxifen treatment for five years can reduce recurrence rates by 41% and mortality rates by 31%. For premenopausal 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.
In patients treated with aromatase inhibitors, it is important to monitor bone mineral density; if osteoporosis develops, calcium and vitamin D supplements should be added, along with bisphosphonates and Prolia (denosumab) if necessary. In patients with premenopausal diagnosis of breast cancer, postmenopausal (physiologic or chemotherapeutic effect) use of aromatase inhibitors remains beneficial.
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, reduces 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, patients may benefit from continued use of tamoxifen.
The International ATLAS (comparing long-term versus short-term adjuvant tamoxifen therapy) study showed that 10 years of tamoxifen reduced late recurrence and mortality in ER+ breast cancer patients compared to 5 years of standard tamoxifen therapy, with better outcomes. 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 may further reduce the risk of recurrence in estrogen receptor-positive breast cancer. Adjuvant treatment with tamoxifen for 10 years reduces the risk of death by at least one-third compared to no tamoxifen.
Chemotherapy
Chemotherapy reduces 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 with surgery and hormone therapy alone. Further research is needed to determine which group of patients needs chemotherapy. We know that molecular tests, such as
Oncotype DX, can predict the prognosis of patients. 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 if a breast cancer patient requires chemotherapy, there is a lot to learn about chemotherapy planning. How to develop a chemotherapy plan that reduces patient mortality and chemotherapy-induced side effects is a current issue to consider.
HER2 Targeted Therapy
The treatment of breast cancer has entered the era of molecular typing, and 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 for 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 postoperative adjuvant therapy for breast cancer suggest that surgery plus the anti-HER2 agent trastuzumab improves DFS rates compared to surgery alone, and most clinical trials have 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 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 less likely to be hormone receptor positive and more likely to be HER2 gene positive.
Treatment of advanced breast cancer
The main goal of chemotherapy for advanced breast cancer is to reduce 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 the treatment.
Depending on the subtype, the median survival after distant metastasis of breast cancer varies, generally ranging from six months to 2.2 years. Over the past 30 years, overall survival for breast cancer patients has improved significantly, especially for HER2-positive breast cancers. Metastatic breast cancer is still incurable, but treatment can be used to improve survival and quality of life.
Hormone therapy
For estrogen receptor-positive metastatic breast cancer, hormone therapy remains the first choice. The choice of hormonal treatment regimen should be based on the patient’s previous response to treatment and whether or not she is menopausal. Drug resistance is common and unavoidable in hormonal treatment of 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 and 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.
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 based on the patient’s medical condition and the nature of the tumor (e.g., triple-negative breast cancer, HER2
positive) and the previous response to chemotherapy. Chemotherapy is usually a short course of treatment, completed in a few cycles. There is no uniform conclusion as to the exact number of courses of chemotherapy needed.
Targeted therapy for HER2
Prior to the advent of targeted drugs, HER2-positive breast cancer patients were considered to have a poor prognosis. With the advent of humanized monoclonal antibodies targeting HER2
humanized monoclonal antibodies, the prognosis of this group of patients has improved significantly. Trastuzumab in combination with paclitaxel has significantly improved survival in neoadjuvant therapy for HER2-positive breast cancer.
Patients with HER2-positive breast cancer who have failed trastuzumab therapy have the option of 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, and the EMILIA study showed that the experimental new drug T-DM1 was better tolerated than 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 patients with HER2-positive metastatic breast cancer has improved significantly over the past 3 years.
Management of breast cancer bone metastases
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 rationale that zoledronic acid inhibits osteoclast-mediated bone resorption.
Denosumab (XGEVA) is a subcutaneously injected monoclonal antibody to XGEVA that binds to RANKL
is 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-related events by this principle.
In a recent randomized controlled study, XGEVA was shown to be more effective in reducing the incidence of bone marrow-related events than zoledronic acid.
Both XGEVA and zoledronic acid can cause hypocalcemia, and care should be taken with calcium and vitamin D. The incidence of osteonecrosis of the jaw in patients treated with XGEVA and zoledronic acid is 0.5%-1%. Therefore, care should be taken to maintain oral hygiene and avoid dental-related procedures while taking these drugs.
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. 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 good results after treatment.
Outlook
At the genetic level, breast cancer is a highly heterogeneous disease. For patients with HER2-positive breast cancer, the introduction of trastuzumab has given hope to this 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.