I. Overview
Breast cancer remains the most common malignancy in women in the U.S. A total of 235,030 women were diagnosed with invasive breast cancer and 40430 patients died from breast cancer nationwide in 2014. An additional 64,640 women were diagnosed with carcinoma in situ (ductal carcinoma in situ and lobular carcinoma in situ) in 2013. While the incidence of breast cancer has steadily increased over the past decade, the mortality rate has declined, thanks to early diagnosis and more effective treatment.
II. Key points of update
There are few updates in this guideline on the management of advanced breast cancer, mainly including.
1. For patients with metastatic breast cancer, the metastases should be biopsied again to determine ER/PR and HER2 status. If biopsy samples cannot be safely obtained, treatment should be based on the ER/PR and HER2 test results of the primary tumor.
2. The optimal regimen for zoledronic acid is once a month, reduced to once every three months after 12 months.
3, Limited studies have shown a benefit in progression-free survival (PFS) with the addition of trastuzumab or lapatinib in postmenopausal patients who are ER, HER2-positive and on aromatase inhibitors, but no evidence of prolonged overall survival (OS).
4. Patients with metastatic breast cancer already treated with chemotherapy and trastuzumab may be considered for a regimen of trastuzumab in combination with patuximab therapy with or without cytotoxic agents (e.g., vincristine, paclitaxel).
III. Disease examination and assessment
1.Patients with suspected breast cancer recurrence or metastasis are recommended to undergo chest CT and abdomen ± pelvis CT or MRI.
2. When patients have central nervous system symptoms, MRI of the brain is recommended.
3.When PET/CT clearly indicates bone metastasis in both PET and CT parts, bone scan or sodium fluoride PET/CT examination may be unnecessary.
4.The expert group does not recommend the use of sodium fluoride PET/CT as a screening tool for breast cancer recurrence and metastasis, unless other tests cannot clearly assess the current disease.
5.First recurrence and suspected metastasis require further tissue biopsy.
6. Genetic counseling should be performed for patients with high risk of hereditary breast cancer.
7. Since ER/PR and HER2 testing of the primary tumor may have false results, re-testing of metastatic foci for ER/PR and HER2 status is recommended, especially in cases of initial unknown or initial negative or not overexpressed.
IV. Treatment of local/regional recurrence
1. Patients with locally recurrent breast cancer should undergo surgical re-excision if possible. If not initially treated with radiation, irradiation of the chest wall, supraclavicular lymph nodes, and subclavian lymph nodes is performed postoperatively. If necessary, systemic treatment should be given first to achieve the best remission rate before surgical resection.
2.For patients with local recurrence who underwent primary local lesion resection, total mastectomy + axillary lymph node dissection was performed.
3.Patients with regional recurrence should all undergo radiation therapy to the chest wall, supraclavicular lymph nodes, subclavicular lymph nodes and corresponding regional lymph nodes.
4. Systemic treatment should be continued after local treatment
V. Treatment of bone metastasis
Bone metastasis is the most common distant metastasis of breast cancer, with an incidence of 49% to 60%. Bone metastasis itself does not pose a direct threat to life, but the bone-related events caused by it can lead to extreme pain and seriously affect patients’ quality of life. Therefore, the treatment of bone metastases is of great importance.
1. For patients with breast cancer bone metastases with expected survival ≥ 3 months and creatinine < 3,0 mg/dl, denosumab, zoledronic acid or pamidronate disodium should be added to the regimen of conventional chemotherapy and endocrine therapy against bone destruction, especially for patients with osteolytic bone metastases and/or weight-bearing bone metastases (Class I recommendation).
2, For osteolytic bone metastases, zoledronic acid is superior to pamidophosphate.
3. Studies have shown that the use of bisphosphonates and denosumab has the potential to cause osteonecrosis of the jaw (incidence about 5,48%), and poorer underlying oral health or dental surgery during drug administration are known risk factors. Therefore, it is recommended that patients undergo dental examination and prophylaxis before receiving intravenous administration of these drugs and avoid dental operations during treatment if possible.
4. No studies have shown an effect of bisphosphonate or denosumab use on overall survival.
5. Calcium and vitamin D should be supplemented while taking bisphosphonates at a daily dose of 1200-1500 mg of calcium and 3400-800 IU of vitamin D.
6. The current study data support a 2-year treatment duration for bisphosphonates.
VI. Endocrine therapy
Patients with ER and/or PR positive advanced breast cancer are suitable for endocrine therapy, which mainly includes non-steroidal aromatase inhibitors (anastrozole and letrozole), steroidal aromatase inhibitors (exemestane), selective estrogen receptor modulators (SERM; tamoxifen, toremifene), selective estrogen receptor downregulators (SERD; fulvestrant); for most patients receiving tamoxifen For most patients with advanced premenopausal breast cancer treated with tamoxifen, ovarian debulking or resection with endocrine therapy regimen is also an appropriate choice.
For premenopausal patients with ER and/or PR positive who have received endocrine therapy within the last 1 year, ovarian debulking or resection with postmenopausal endocrine therapy regimen is recommended; premenopausal patients who have not received endocrine therapy within 1 year can also be treated with SERM (tamoxifen, toremifene).
2. Postmenopausal patients with ER and/or PR positive who have received endocrine therapy within the last 1 year can continue the original regimen until disease progression; postmenopausal patients who have not received endocrine therapy within 1 year are recommended to be treated with aromatase inhibitors (AI; anastrozole, letrozole or exemestane) or SERM (tamoxifen, toremifene) or SERD (fulvestrant).
3. Because of the possibility of false-negative ER/PR tests, patients with metastatic breast cancer with non-visceral metastases or asymptomatic visceral metastases may still be considered for endocrine therapy even if they are hormone receptor negative, especially in patients with clinical features suggesting the possibility of hormone receptor positivity (e.g. long disease-free survival, limited recurrent foci, slowly progressing lesions, advanced age, etc.).
4, A phase III clinical trial demonstrated a benefit in progression-free survival (PFS) with 500 mg fulvestrant versus 250 mg dose (HR0, 8), and the final analysis showed a 4, 1 month prolongation in median overall survival (OS) (26, 4: 22, 3) and a 19% reduction in the risk of death (HR0, 81).
5. For postmenopausal patients with recurrent breast cancer who have been treated with anti-estrogen drugs and have been on them for no more than 1 year, there is evidence to support the use of AI as a first-line treatment option.
6. One of the mechanisms of endocrine therapy resistance in breast cancer is the activation of the mammalian target of rapamycin (mTOR) signaling pathway. An intentional analysis showed a greater advantage of tamoxifen in combination with everolimus than tamoxifen alone in the treatment of patients with endocrine drug resistance (PFS 8, 5m: 4, 5m). However, in another BOLERO-2 trial, there was no difference in the results of letrozole combined with everolimus versus letrozole alone. The reason for the inconsistent results of the two trials is unknown and may be related to the degree of prior endocrine therapy and the type of drug the patients received.
The BOLERO-2 trial showed that exemestane combined with everolimus significantly prolonged PFS in postmenopausal hormone receptor-positive breast cancer patients with recurrence or progression after treatment with nonsteroidal aromatase inhibitors, and the panel strongly recommended that patients who met the BOLERO-2 enrollment criteria be treated with the above regimen.
VII. Chemotherapy and targeted therapy
The guidelines recommend that patients with advanced breast cancer who are hormone receptor negative, whose metastases are not confined to bone or soft tissue and have significant symptoms, or who are hormone receptor positive but have failed endocrine therapy may receive chemotherapy.
1. In single-agent regimens, eribulin is indicated for patients with metastatic breast cancer who have received at least two previous chemotherapy regimens containing anthracyclines and paclitaxel. Eribulin has a greater advantage in OS and PFS compared to the rest of single-agent regimens.
2. The first-line regimen for HER2-positive patients with advanced breast cancer is patuximab + trastuzumab + docetaxel (a Class I recommendation) or patuximab + trastuzumab + paclitaxel.
3. For patients with advanced disease who have been treated with trastuzumab, T-DM1 therapy is recommended.
VIII. Summary
There are many treatment options for advanced breast cancer, and despite the large number of clinical use as a basis, there is still no single option that can achieve maximum efficacy and minimum toxicity, so patients should not be satisfied with just accepting the current level of treatment. It is the responsibility of both the patient and the clinician to explore the most appropriate therapeutic approach.