There are approximately 1.2 million new breast cancer cases and about 500,000 deaths worldwide each year. In China, the number of patients newly diagnosed with breast cancer has increased to nearly 170,000 each year, and 50% of breast cancers will recur or develop metastases with a median survival time of about 2 years. The number of deaths is nearly 40,000.
The principles of treatment for recurrent metastatic breast cancer are to control the disease progression and improve the patient’s quality of life and prolong survival. Clinical studies have shown that the overall survival of patients with persistent stable disease for more than 6 months after treatment is the same as that of patients who achieved clinical remission. Therefore, patients with advanced disease should be considered clinically beneficial if their disease remains stable for a long time after treatment. Treatment mainly includes chemotherapy and endocrine therapy and biologically targeted therapy. Which treatment is preferred after relapse depends on the hormone receptor status of the patient’s tumor tissue (ER/PgR), Her-2 results, age, menstrual status and whether the disease is progressing slowly. In principle, endocrine therapy can be preferred for hormone-responsive breast cancer patients with slow disease progression; chemotherapy should be preferred for patients with recurrent metastases with rapid disease progression; and Her-2 overexpressed patients can be considered for treatment with trastuzumab (Herceptin) alone or in combination. After failure of a particular treatment, a rational sequential use of chemotherapy and endocrine therapy is advocated.
Endocrine therapy: Different classes of endocrine drugs can be applied sequentially in the relatively slow stage of disease progression. In 2006, SABCS reported the results of the EFECT study, in which 693 patients with recurrent or metastatic postmenopausal receptor-positive non-steroidal AI therapy who failed were randomly divided into two groups. The results showed that the ORR was 7.4% and 6.7% in the treatment and control groups, respectively (Ρ=0.7364); the clinical benefit rate was 32.2% and 31.5% in the two groups, respectively (Ρ= 0.8534)
When two or three endocrine agents have failed, chemotherapy should also be switched. In principle, chemotherapy is preferred in premenopausal patients with recurrent metastatic breast cancer. If chemotherapy fails or cannot be tolerated, luteinizing hormone-releasing hormone analogs such as goserelin (Norelide) can be used to perform pharmacological ovarian debulking and then combined with aromatase inhibitor therapy.
Principles of chemotherapy drug selection for recurrent metastatic breast cancer: Generally speaking, if recurrence or metastasis occurs more than 1 year after adjuvant or first-line treatment, the relief regimen can still be used similar to the original regimen; if recurrence or metastasis occurs soon after adjuvant or first-line regimen chemotherapy, a different regimen should be considered.
Drugs recommended for chemotherapy of metastatic breast cancer include: anthracyclines, paclitaxel, capecitabine, vincristine, and gemcitabine.
Different treatment regimens can be used according to the different conditions of recurrent metastatic breast cancer.
1.Patients with previous adjuvant treatment with endocrine therapy only and no chemotherapy
Such patients can choose CMF or CAF regimen. Anthracyclines are still one of the drugs of choice for the treatment of advanced breast cancer due to their precise efficacy and low price. In previously untreated patients with advanced disease, the effectiveness of adriamycin alone is 38% to 50%; in previously treated patients, the effectiveness of ADM is 30%. Combination chemotherapy regimens containing anthracyclines are one of the standard treatments for advanced breast cancer and are more effective than traditional CMF regimens, but because anthracyclines are widely used in the adjuvant treatment of breast cancer, the reuse of anthracyclines in recurrent metastatic breast cancer is Anthracyclines are less likely to be used again in recurrent metastatic breast cancer.
2. Patients who have not been treated with anthracycline and paclitaxel chemotherapy in adjuvant therapy
Patients who have failed in adjuvant therapy of CMF, anthracycline combined with paclitaxel is preferred; some patients who have used anthracycline and/or paclitaxel chemotherapy in adjuvant therapy but have not been clinically determined to be resistant and have failed in treatment can also use adriamycin combined with paclitaxel. Due to their unique mechanism of action and high efficacy, paclitaxel drugs are now widely used in the treatment of advanced breast cancer. For the first-line treatment of breast cancer, the efficiency of paclitaxel (PTX) is 32%-56%, and that of polyene paclitaxel (TXT) is 54%-67%. Paclitaxel alone or in combination with anthracyclines is the standard first-line chemotherapy regimen for metastatic breast cancer, and the first-line efficacy in combination with anthracyclines: 55-63%, median TTF 7.8 months.
Due to the widespread use of paclitaxel in adjuvant therapy, there are now relatively more data supporting the use of TXT in salvage therapy. the TAX311 trial compared PTX and TXT in metastatic breast patients who failed adriamycin therapy. The results showed that the TXT group was slightly more effective (32% vs. 25%, P=0.10); there was a significant advantage in the TXT group in terms of TTP (5.7 months vs. 3.6 months, P=0.0001) and OS (15.4 months vs. 12.7 months, P=0.03); and both hematologic and non-hematologic toxicities were higher in the TXT group than in the PTX group for treatment.
Two recent multicenter clinical studies have demonstrated the survival advantage of two combination chemotherapy regimens.
(1) Capecitabine combined with polyene paclitaxel (XT) regimen In anthracycline-resistant breast cancer, polyene paclitaxel is one of the most effective agents for monotherapy (19%-57%). Capecitabine has an efficiency of 15%-25% on its own.
(2) Gemcitabine combined with paclitaxel (GT) regimen In advanced breast cancer, the remission rate of gemcitabine alone is 25%-46%, and the efficiency of PTX is 6%-47%, a multicenter phase III clinical study included 529 patients who had been treated with anthracycline chemotherapy, 267 of which were treated with PTX (175mg/m2d1) + gemcitabine (1250mg/m2, d1,8) and 262 with PTX (175mg/m2d1). , 8) regimen and 262 cases with PTX alone, both repeated at 3 weeks. The results showed that the medium TTP was 5.4 and 3.5 months in the combination and single drug groups, respectively; the effective rates were 39.3% and 25.6%, respectively; and the median overall survival was 18.5 months and 15.8 months, respectively. Therefore, the US FDA approved the GT regimen in 2004 for the first-line treatment of metastatic or recurrent breast cancer.
After the failure of anthracycline, the above two regimens were compared with similar results. The efficacy rate was similar (42% vs. 39.3%) and the median TTP was close (6.1 months vs. 5.4 months), but the XT regimen had greater adverse effects and required dose reduction in about 2/3 of patients in clinical use.
(3) Paclitaxel combined with capecitabine
Docetaxel combined with capecitabine can prolong the survival of patients with metastatic breast cancer, but with higher toxicity. The results of a phase II clinical study of paclitaxel combined with capecitabine for metastatic breast cancer showed that paclitaxel combined with capecitabine was more efficacious and tolerable. Based on this, Lueck et al. conducted a randomized multicenter controlled study of paclitaxel in combination with capecitabine (XP) versus paclitaxel in combination with epi-adriamycin (EP) for the first-line treatment of advanced breast cancer, the results of which were reported at the ASCO meeting, with 60 mg/m2 of adriamycin and 175 mg/m2 of paclitaxel in the EP group, d1, repeated every 21 days for 6 cycles. The XP group: capecitabine 1000 mg/m2 twice a day, d1-14 and paclitaxel 175 mg/m2, d1, repeated every 21 days for 6 cycles. As a result, there was no significant difference in PFS (11.8 months vs. 12.3 months), ORR (41.0% vs. 41.5%) and overall survival rate; in terms of toxic side effects, there were 5 cases of febrile granulomatous deficiency and 2 cases of cardiotoxicity discontinuation in the EP group; 1 case of febrile granulomatous deficiency and 4 cases of gastrointestinal toxicity in the XP group. It is suggested that paclitaxel combined with capecitabine is comparable to anthracycline combined with paclitaxel in the first-line treatment of metastatic breast cancer, with less toxic side effects, and can be an option for patients with metastatic breast cancer who have received anthracycline treatment before.
4. Patients who failed paclitaxel treatment
There is no standard regimen recommended yet. The drugs that can be considered are capecitabine, vincristine (the efficiency of monotherapy for metastatic breast cancer is 35% to 50%), gemcitabine, platinum and new chemotherapy drugs such as Epothilone, Al, etc., which are taken as monotherapy or combination chemotherapy. Combination chemotherapy can be either vincristine combined with cisplatin (NP regimen), or gemcitabine combined with cisplatin (GP regimen).
In such patients, there is no uniformity in the dose and duration of relief chemotherapy. Recent data show that high-dose chemotherapy has not shown a better palliative treatment effect compared to conventional chemotherapy. The optimal duration of chemotherapy is unclear. The results of randomized group studies suggest that chemotherapy for 6 months may be more effective compared with shorter courses, while chemotherapy beyond 6 months can prolong TTP but also increases treatment-related toxicity and does not significantly prolong patient survival; therefore, one current treatment strategy is to discontinue chemotherapy after 1 to 2 cycles of chemotherapy after achieving CR or PR. When tumor progression occurs, the next course of chemotherapy is then considered. Randomized group trials have demonstrated that this treatment strategy is as effective as continuous chemotherapy with lower toxicity; another treatment strategy is to take different means of sequential treatment, such as maintenance with endocrine therapy after achieving remission with chemotherapy.
Targeted therapy.
HER-2-positive MBC.
1, trastuzumab combined with endocrine therapy
The efficiency of Herceptin monotherapy for recurrent metastatic breast cancer was 15%-30%. 207 postmenopausal HER2-positive and estrogen receptor (ER)/progesterone receptor (PR)-positive metastatic breast cancer patients were enrolled in the TAnDEM study, and the treatment group received trastuzumab weekly regimen combined with anastrozole and the control group received anastrozole monotherapy. The results showed that in terms of PFS, the median survival was 4.8 and 2.4 months in the treatment and control groups, respectively (P=0.0016); the median survival was 28.3 and 23.8 months in the treatment and control groups, respectively, therefore, the use of anastrozole in combination with trastuzumab significantly prolonged PFS in HER2-positive, hormone receptor-positive metastatic breast cancer patients, in which those receiving the combination regimen The PFS in the group treated with the combination regimen exceeded 2 years by 15%, which also predicted that this group of patients would be likely to delay chemotherapy.
2. Trastuzumab + chemotherapy
The results of the BCIRG-007 study showed that adding carboplatin to trastuzumab in combination with docetaxel did not prolong TTP or overall survival. However, the M016419 CHAT study came to the opposite conclusion. 225 patients with HER2-positive metastatic breast cancer were enrolled and randomized into two groups, treatment group: trastuzumab 8 mg/kg d1, 6 mg/kg every 3 weeks from week 4, combined with docetaxel 75 mg/m2 d1 + capecitabine 950 mg/m2Bid, d1-14, repeated at three weeks . The control group had the same trastuzumab usage, combined only with single agent docetaxel 100mg/m2d1, repeated for three weeks. The results showed that OR was similar in both groups, 71% and 73% in the treatment and control groups, respectively, but median PFS, was prolonged by 2 months in the treatment group compared to the control group (14.8 months versus 12.8 months, P=0.06); in terms of median TTP, 18.2 months and 13.8 months in the treatment and control groups, respectively (P=0.04).
Therefore, trastuzumab combined with docetaxel + capecitabine is appropriate for HER2-positive metastatic breast cancer patients in good general condition.
3. Trastuzumab in combination with bevacizumab
At the 2006 SABCS meeting, Pegram et al. reported the results of a phase II clinical study of bevacizumab in combination with trastuzumab in patients with HER2-positive metastatic breast cancer. 37 patients with HER2-positive metastatic breast cancer, 62% with visceral metastases and 62% ER and/or PR positive, were treated with trastuzumab 4 mg/kg, d1, 2 mg from week 2 onwards. The results were 2.7% for CR and 51.4% for PR with trastuzumab 4 mg/kg, d1, 2 mg once a week from week 2, combined with bevacizumab 10 mg/kg, d7, once every 2 weeks. In terms of toxic side effects, there were 9 adverse events, including 7 cases of hypertension, 1 case of dyspnea, 1 case of proteinuria, and only 1 grade 4 adverse event of reduced left ventricular ejection fraction. Therefore, the efficacy of bevacizumab in combination with trastuzumab for HER2-positive recurrent/metastatic breast cancer deserves further study.
4. lapatinib in combination with capecitabine
At the ASCO meeting, lapatinib received a lot of attention as a new tyrosine kinase inhibitor. Unlike other tyrosine kinase inhibitors, lapatinib can act on both EGFR (HER1) and HER2 (ErbB-2) targets, and this mode of action has a much greater biological effect in inhibiting tumor cell proliferation and growth than inhibiting only one of these targets. At the 2006 ASCO meeting, Geyer reported the results of an international, randomized, open phase III clinical study in which 321 patients with metastatic breast cancer with high Her-2 expression and resistance to trastuzumab were treated with capecitabine or capecitabine in combination with lapatinib, with 160 patients in the treatment group receiving oral lapatinib: capecitabine In the control group, 161 patients received capecitabine 1250 mg/m2 orally for 3 weeks, Bid×14 days. The results showed that the median time to tumor progression (TTP) was 19.7 weeks in the control group, compared with 36.9 weeks in the treatment group (P=0.00016), almost doubled.