The 2nd Conference on Individualized Treatment of Breast Cancer was successfully held in Beijing from August 1 to August 3, 2014. With the theme of “Breast Cancer Prevention and Treatment, Tailor-made”, the conference focused on the development of individualized and precise treatment for breast cancer patients, and established a high-level communication platform for scholars and doctors in basic and clinical research related to breast cancer. During the conference, Prof. Andrew D. Seidman from Memorial Sloan D. Kesselring Cancer Center gave a presentation on the topic of “DD Science and Art of Personalized Chemotherapy Strategy for Metastatic Breast Cancer”. Yang Xiaobing, Department of Oncology, Guangdong Chinese Medicine Hospital
What is “the integration of science and art”?
Professor Seidman pointed out at the beginning of the presentation that the clinical treatment of metastatic breast cancer has the characteristics of “fusion of science and art”. The so-called “science” refers to clinical research data, while the so-called “art” is based on the individualized treatment after considering the biological characteristics and aggressiveness of the tumor, the patient’s previous treatment, as well as his or her symptoms, comorbidities and preferences. The choice is individualized based on the biology and aggressiveness of the tumor, the patient’s previous treatment, and the patient’s symptoms, comorbidities and preferences. As one of the most difficult diseases to cure, patients with metastatic breast cancer often have systemic symptoms and therefore deserve special attention for their quality of life throughout the treatment period.
For patients with estrogen receptor (ER)/progesterone receptor (PR)-negative or ER/PR-positive breast cancer who have failed endocrine therapy, current National Comprehensive Cancer Network (NCCN) clinical practice guidelines for breast cancer recommend chemotherapy. An earlier meta-analysis of advanced breast cancer showed that combination chemotherapy was more effective than monotherapy. However, Professor Seidman pointed out that the meta-analysis had some shortcomings, such as the small number of patients and deaths, the lack of paclitaxel in the combination regimen, and the inclusion of studies involving only first-line treatment of breast cancer. In fact, patients with metastatic breast cancer are often treated with multiple lines of therapy, and the treatment process is like a story with many chapters, with various single-agent regimens, multiple combination regimens, or both interspersed throughout. This requires clinicians to be guided by science and to make individualized artistic choices for their patients.
Interpreting scientific data and thinking about individualized treatment
Before making individualized choices, it is important to first identify which patients are suitable for combination therapy? Studies have shown that combination chemotherapy can be preferred for young patients with good tolerability, visceral metastases, and rapid tumor progression (e.g. short recurrence-free interval after adjuvant chemotherapy, lack of sustained efficacy of previous single-agent chemotherapy, and rapid “volume” growth of tumor). In a 2008 clinical study, gemcitabine combined with paclitaxel (GT) in first-line treatment of patients with metastatic breast cancer had significantly longer overall survival (OS, 18.6 months vs. 15.8 months, P=0.0489) and time to disease progression (TTP) (6.14 months vs. 3.98 months, P=0.0002), and the objective remission rate (ORR, 41.4% vs. 26.2%, P=0.0002) in the combination treatment group. P=0.0002) were also better in the combination group. Patients tolerated both regimens generally well, with more hematologic toxicities in the combination group, but the absolute number of cases was not high.
In 2009, Chan et al. compared the efficacy of gemcitabine + docetaxel (GD) with capecitabine + docetaxel (CD) in patients with advanced breast cancer previously treated with anthracyclines. The results showed no significant differences in ORR (both 32%) and PFS (8.05 months versus 7.98 months, P=0.121) between the two groups, drug-related discontinuation rates were twice as high in the CD group as in the GD group (27% versus 13%), and grade 3/4 hematologic toxicities were comparable in both groups, but non-hematologic toxicities such as hand-foot syndrome, diarrhea, and mucositis were significantly higher in the CD group. The study suggested that the GD regimen was comparable to the CD regimen in patients with advanced breast cancer who had previously used anthracyclines, but the former was better tolerated.
On this basis, a study conducted by Prof. Seidman in 2010 further evaluated the difference in efficacy of single-agent sequential therapy after chemotherapy with the two drugs mentioned above. Patients with advanced breast cancer were randomized to receive GD or CD induction therapy, and when progression occurred crossed over to another group receiving either gemcitabine (CD→G group) or capecitabine monotherapy (GD→C group). The results showed that there was no significant difference in TTP1 between the GD and CD groups during the induction treatment period (9.3 months versus 8.9 months, P=0.387); nor was there a significant difference in TTP2 between the GD→C and CD→G groups during the subsequent crossover treatment period (4.5 months versus 2.3 months, P=0.149). Exploratory analysis showed that total TTP was 5.1 months longer in the GD→C group compared with the CD→G group during the induction + crossover period (14.3 months versus 9.2 months, P=0.094). There was no significant difference between groups in either overall population ORR (GD: 34.8% versus CD: 40.8%, P=0.216) or crossover treatment population ORR (GD→C: 15.3% versus CD→G: 7.1%, P=0.184). The toxicity and safety of the two-drug chemotherapy regimen shown in this study were also consistent with previous studies. Although hematologic toxicity was higher in the GD group than in the CD group during the induction phase, the incidence of grade 3/4 granulocytopenic fever was comparable in both groups. In contrast, grade 3/4 non-hematologic toxicity was more pronounced in the CD group, with more patients experiencing hand-foot syndrome or mucositis and a higher rate of discontinuation due to drug-related toxicity (28.4% versus 18.0%, P=0.009).
A recent pooled analysis published in Oncologist pooled patient data from the two aforementioned independent studies to further clarify the differences in efficacy between GD and CD regimens for metastatic breast cancer and to explore subgroups of the population that may benefit from the different regimens. The results showed no significant differences in OS [21.5 months versus 22 months, hazard ratio (HR)=1.02, P=0.824] and progression-free survival (PFS, both 8.5 months, HR=1.15, P=0.79) between the GD and CD regimens in the overall population. In the pooled crossover subgroup population, there was a trend for the GD→C regimen to prolong patient OS (25.5 months versus 23.5 months, HR=0.82, P=0.171) and TTP (8.3 months versus 6.5 months, HR=0.93, P=0.557) compared to the CD→G regimen.
Professor Seidman noted that because the dose of capecitabine is correlated with safety, and treatment-related adverse events were reduced by capecitabine dose reduction at the time of single-agent sequencing in the 2010 study mentioned above, a pooled safety analysis of two studies with different capecitabine doses appears somewhat unreasonable. However, the studies still provide some clinical safety references, such as the significantly higher rate of drug toxicity-related discontinuations in the CD group compared with the GD group in the 2010 study (28.4% versus 18.0%, P=0.009), a result consistent with the study conducted by Chan (27% versus 13%), suggesting a significantly higher rate of toxicity-related discontinuations in patients receiving the CD regimen compared with the GD regimen. This pooled analysis confirmed that the GD regimen was comparable in efficacy to the CD regimen, both in the overall population, in the crossover population, and in all subgroups of the population tested, but that the CD regimen had a higher discontinuation rate. Patient Eastern U.S. Collaborative Oncology Group (ECOG) physical status (PS) scores, ER status, prior adjuvant paclitaxel therapy, and number of lesion metastases were associated with improved OS and PFS in the overall population. Therefore, for clinicians to improve treatment adherence, in addition to focusing on efficacy, patients should be considered for tolerance to drug toxicity.
Exploration of maintenance therapy for advanced breast cancer
For patients with advanced breast cancer whose tumors are in remission or whose disease is stable after the end of first-line chemotherapy, should they continue maintenance chemotherapy or wait and see? How long is maintenance chemotherapy sufficient? This has been explored by Korean scholars. In the study, 324 patients with metastatic breast cancer not previously treated with chemotherapy received 6 cycles of paclitaxel + gemcitabine (PG) chemotherapy to achieve complete remission (CR), partial remission (PR), or stable disease (SD), and then were randomized to receive PG maintenance chemotherapy or observation until disease progression. at the end of 6 cycles of PG treatment, patients had an ORR of 50% and disease control rate (DCR. CR+PR+SD) reached 78.6%, with 231 cases eventually entering the randomized group. Data showed that PG maintenance therapy significantly prolonged patient PFS by up to 3.7 months (7.5 months versus 3.8 months, P=0.026), increased 6-month PFS rate (59.7% versus 36.0%, P=0.00023), and prolonged median OS (36.8 months versus 28.0 months, P=0.048, Figure) compared to wait-and-see. Subgroup exploratory analysis showed that the subgroup of patients who were premenopausal, ≤50 years old, treated to CR or PR, visceral metastases, hormone receptor negative, and ≥2 metastases benefited more from PG maintenance therapy. Not surprisingly, adverse events were higher in the maintenance group than in the observation group, but overall maintenance therapy was well tolerated and toxicities were manageable, and quality of life (QOL) was comparable in both groups.
Over time, patients receiving chemotherapy experienced a gradual reduction in symptoms associated with chemotherapy, but also a gradual increase in chemotherapy-related toxicities. When the cumulative toxicity is about to exceed the treatment benefit, timely intervention by clinicians is required. To alleviate or at least maintain existing symptoms while reducing drug toxicity, combination chemotherapy should be stopped and switched to monotherapy when appropriate. Currently, to ensure quality of life, patients on combination therapy are primarily switched to a maintenance strategy of targeted monotherapy after disease remission is achieved. In the future, sequential receipt of better tolerated chemotherapeutic agents or immunotherapy may become a new trend in treatment. As a cell cycle-specific antitumor agent, gemcitabine exerts its antitumor effects by impeding intracellular DNA replication, inhibiting DNA synthesis, and enhancing intracellular activity. The unique mechanism of action allows it to be combined with other drugs without cross-resistance. A practical example in clinical practice shows that patients with advanced breast cancer who have achieved remission with PG chemotherapy are significantly relieved from some toxic symptoms such as hair loss and fatigue if they receive subsequent maintenance treatment with gemcitabine.
Summary]
Professor Seidman concluded by pointing out that to improve chemotherapy regression in patients with metastatic breast cancer and to select the best treatment plan for patients, personalized artistic processing based on scientific data is required. As clinicians, they should not only identify the genetic characteristics of patients and their tumors, but also gain insight into the resistance mechanisms and toxicity responses of different drugs and develop appropriate strategies to address them. In addition, clinicians should actively develop better biological markers to improve the prediction of patient response to therapy.