In 2013, breast cancer remained the most common tumor in women, with incidence rates continuing to rise. But mortality rates are declining, brought about in part by earlier diagnosis through screening mammography, improved surgical techniques, a focus on cutting edges, improvements in radiation therapy, and better adjuvant therapy.
Adjuvant treatment 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 micrometastatic lesions. About 80% of breast cancer patients are estrogen receptor positive, and these patients can reduce their relative risk of recurrence by 41% and the risk of death from breast cancer by 31% with 5 years of adjuvant tamoxifen treatment. Tamoxifen remains the standard of care for premenopausal women.
For postmenopausal women, aromatase inhibitors have been shown to be superior to tamoxifen. Two large trials (ATAC and BIG1-98) involving 10,000 women compared the efficacy of 5 years of aromatase inhibitors to 5 years of tamoxifen with 5.8 years of follow-up. The aromatase inhibitor group showed an absolute reduction in risk of recurrence of 2.9% (p<0.001), although the absolute improvement in overall survival was relatively small. Patients with premenopausal diagnosis of breast cancer who later became postmenopausal (naturally or as a result of chemotherapy) would benefit from switching to an aromatase inhibitor after 2 to 3 years of tamoxifen. < p="">
Adjuvant hormone therapy after 5 years
In patients with estrogen receptor-positive breast cancer, many recurrences occur after 5 years. For women completing 5 years of tamoxifen treatment, being in postmenopause and then using the nonsteroidal aromatase inhibitor letrozole for 5 years reduces the relative risk by 42% (p<0.001). For premenopausal women who have completed 5 years of tamoxifen therapy or who are intolerant of aromatase inhibitors, recent evidence suggests that there is also a benefit to re-administering continuous tamoxifen therapy. < p="">
The ATLAS trial enrolled nearly 7,000 estrogen receptor-positive early-stage breast cancers, and continued tamoxifen treatment up to 10 years further reduced the risk of recurrence and breast cancer mortality. In a recent meta-analysis that included five clinical trials on expanded adjuvant tamoxifen therapy (>20,000 women), the absolute risk reduction was 2.1% and 4.1% for lymph node-negative and positive women, respectively. An increased risk of endometrial cancer was observed in women on continuous tamoxifen treatment (3.1% vs 1.6%). similar results were observed in the ATTom trial involving 6953 women. Pooled data on ATLAS and ATTom confirmed that 10 years of adjuvant tamoxifen treatment, compared to no endocrine therapy, reduced breast cancer mortality by 1/3 in the first 10 years of follow-up, with continued benefit after 10 years. Continued adjuvant endocrine therapy for 10 years has become a standard option, especially for patients with initial lymph node positive breast cancer.
Chemotherapy
Combining adjuvant chemotherapy reduces the relative risk of breast cancer mortality by approximately 1/3, with the absolute risk reduction depending on the risk of recurrence. However, in many patients receiving adjuvant chemotherapy, the improvement in survival is relatively small, as the chances of achieving a cure with surgery and hormone therapy alone are still high. The selection of patients who do need chemotherapy is the main area of research. Molecular tests such as Oncotype DX have improved the prediction of prognosis and can help determine which patients can be cured with hormonal therapy and surgery. In fact, many patients have already obtained an intermediate outcome with these molecular tests and the treatment of these patients became the object of study in large clinical trials for which data are yet to be published (TAILORx (NCT00310180) and MINDACT (NCT00433589)). Recent studies are also exploring ways to optimize chemotherapy regimens to reduce the complications of chemotherapy, and these regimens are increasingly being used worldwide. There are also acute side effects, and many chemotherapy regimens for breast cancer are associated with a lower risk of secondary myeloid tumors and cardiomyopathy.
HER2-targeted therapy
Approximately 15% of breast cancer patients have HER2 gene amplification, and patients with these tumors have an otherwise worse prognosis, and 1 year of trastuzumab therapy improves PFS and OS. trastuzumab side effects are rare, with 3% of patients experiencing decreased left ventricular function, but are usually reversible. It is possible to interrupt trastuzumab therapy and start ACEI drugs, which can restart cardiac function in many patients with LV insufficiency and complete the entire course of trastuzumab.
Bisphosphonates
A recent meta-analysis that included 36 randomized controlled trials found that bisphosphonate therapy resulted in a lower risk of recurrence in postmenopausal breast cancer patients; 11,000 postmenopausal patients were included in this analysis, and bisphosphonate patients had a lower risk of distant recurrence (18.4% vs 21.9%, p<0.001) and a lower risk of bone recurrence (5.9% v 8.8%; p< 0.001). At present, the evidence in this area has not shifted to the routine use of bisphosphonates for this purpose alone. < p="">
Neoadjuvant therapy and locally advanced breast cancer
Patients with large tumors who are not currently candidates for surgery may have their tumors downstaged with preoperative chemotherapy, HER2-targeted therapy, or endocrine therapy to promote operability in breast cancer patients. Neoadjuvant therapy also provides an opportunity to assess the patient’s sensitivity to systemic therapy by testing response during neoadjuvant therapy. Patients who achieve complete pathologic remission, especially in estrogen receptor-negative breast cancer, have an excellent prognosis.
Patients with locally advanced breast cancer can start chemotherapy for tumor reduction prior to surgery. Inflammatory breast cancers that present with erythema and edema are less likely to be hormone receptor positive and more likely to be HER2 positive than non-inflammatory breast cancers. Optimal treatment is usually a multidisciplinary approach with preoperative chemotherapy followed by surgery or radiation therapy (or both).
Treatment of advanced breast cancer
The goal of systemic therapy for advanced breast cancer is to relieve symptoms, control disease, improve overall survival, and minimize the toxicity of treatment. Median survival after distant metastases varies by breast cancer subtype, from 2.2 years for luminalA to 0.5 years for basal-like breast cancer. Overall survival has greatly improved over the past three decades, especially in HER2-positive breast cancer. Metastatic breast cancer is still incurable, but some patients can survive for many years with a better quality of life.
Hormone Therapy
For patients with hormone receptor-positive metastatic breast cancer, hormone therapy is recommended as first-line treatment in the absence of life-threatening visceral disease. The choice of hormonal therapy is dependent on prior treatment and menopausal status. Resistance to hormone therapy is inevitable in metastatic disease, and recent studies have attempted to restore sensitivity. The enzyme mTOR is active in many estrogen receptor-positive tumors that are resistant to hormone therapy. Everolimus in combination with exemestane greatly prolonged disease control compared with exemestane and placebo (PFS 10.6 vs 4.1 months; p<0.001). Everolimus is approved for the treatment of advanced hormone receptor-positive, her2-negative breast cancer in Europe and North America. Phase 1-iii studies using targeted therapy to inhibit other pathways similar to mtor are ongoing. < p="">
Chemotherapy
Chemotherapy is used to target hormone receptor-negative patients with hormone resistance, patients with rapidly progressive disease, and HER2-positive patients regardless of estrogen receptor status. The choice of chemotherapy regimen depends on patient factors (e.g., physical status, comorbidities), acceptable potential toxicity such as alopecia, tumor factors (e.g., triple negative, HER2-positive), duration and responsiveness of prior chemotherapy. Fixed cycles of chemotherapy are usually given, especially for regimens that can produce toxicity, although there are some regimens that extend the cycle (e.g., paclitaxel and capecitabine). There is no consensus on the optimal duration of chemotherapy.
A lot of progress has been made by targeting HER2. In the phase III study, more than 800 patients were randomly assigned to receive docetaxel, trastuzumab, and patuximab, or docetaxel, trastuzumab, and placebo, with the former improving time to disease control by 6.1 months (18.5 vs 12.4 months; p<0.001) and overall survival. The addition of patuximab somewhat increased the side effects of diarrhea and infection. In the phase iii emilia study, t-dmi treatment was better tolerated compared to standard lapatinib and capecitabine treatment, which also improved disease control rates and overall survival