SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately, 231,840 new cases of invasive breast cancer will be diagnosed in 2015 and over 40,000 women will die of the disease.Estrogen Receptor (ER) positive breast cancer cells are driven by estrogens. Tamoxifen is a nonsteroidal Selective Estrogen Receptor Modulator (SERM) and works mainly by binding to the Estrogen Receptor and thus blocks the proliferative actions of estrogen on the mammary tissue. Anastrozole is a non-steroidal Aromatase Inhibitor that binds reversibly to the aromatase enzyme and inhibits the conversion of androgens to estrogens in the extra-gonadal tissues. Aromatase Inhibitors such as ARIMIDEX® have been proven to be superior to Tamoxifen, as adjuvant therapy, in postmenopausal patients with hormone receptor positive breast cancer. It was however not known whether ARIMIDEX® was superior to Tamoxifen in preventing the recurrence of breast cancer.
NSABP B-35 is a randomized phase III trial which compared ARIMIDEX® to Tamoxifen, in preventing the recurrence of breast cancer, in postmenopausal women with Ductal Carcinoma In Situ (DCIS), who underwent lumpectomy and radiation therapy. Of the 3,104 patients who were enrolled and randomized, 1552 patients received ARIMIDEX® 1 mg PO daily and 1552 patients received Tamoxifen 20 mg PO daily. Treatment was continued for 5 years. Enrolled patients had tumors with no invasive component, Estrogen or Progesterone Receptors were positive and margins of resection were clear. The primary endpoint was Breast Cancer-Free Interval (BCFI), defined as the time from randomization to any breast cancer event including local, regional, or distant recurrence or contralateral invasive cancer or DCIS. With a median follow up of 8.6 years, the 10 year Breast Cancer–Free Interval rates were 93.5% with ARIMIDEX® versus 89.2% with Tamoxifen, and this was statistically significant (HR=0.73, P=0.03). This benefit was more so in women less than 60 years of age, with a Breast Cancer–Free Interval rates of 94.9% with ARIMIDEX® and 88.2% with Tamoxifen (HR=0.52, P=0.003). However, in women over 60 years of age, there were no significant differences in outcomes noted between the ARIMIDEX® and Tamoxifen groups. The incidence of invasive contralateral breast cancer was reduced by 45% (HR=0.55, P=0.03) in the ARIMIDEX® group, compared to Tamoxifen group. Adverse events were less common with ARIMIDEX® compared to Tamoxifen. The authors concluded that for postmenopausal women with DCIS treated with lumpectomy and radiation, the 10 year Breast Cancer–Free Interval rates are significantly higher with 5 years of ARIMIDEX® than Tamoxifen and ARIMIDEX® may also be a consideration for those women, who are concerned about the risk of thromboembolic events and uterine cancer with Tamoxifen treatment. Primary results, NRG Oncology/NSABP B-35: A clinical trial of anastrozole (A) versus tamoxifen (tam) in postmenopausal patients with DCIS undergoing lumpectomy plus radiotherapy. Margolese RG, Cecchini RS, Julian TB, et al. J Clin Oncol 33, 2015 (suppl; abstr LBA500)
ABRAXANE® (Nab-paclitaxel) is a solvent free, albumin-encapsulated nanoparticle formulation of the taxane, Paclitaxel. By virtue of its formulation, unlike TAXOL®, hypersensitivity reactions are uncommon with ABRAXANE® and can therefore be rapidly infused and premedications are not needed. Further, higher tumor drug concentrations are achieved with ABRAXANE® compared to conventional Paclitaxel (TAXOL®). Previously published studies have shown that ABRAXANE® is superior to TAXOL® in metastatic breast cancer. GeparSepto trial is a randomized phase III study in which weekly ABRAXANE® was compared head to head with weekly TAXOL® in a neoadjuvant setting. This study enrolled 1204 treatment naïve, high risk patients, with clinical T2-T4d invasive breast carcinoma. Eligible patients included those with unilateral, bilateral, operable or inoperable breast cancer. The median age was 49 years, median tumor size was 3 cm, 23% of the patients had triple-negative disease and 33% had HER-2 positive tumors. Patients were randomized 1:1 to receive either ABRAXANE® 125 mg/m2 IV or TAXOL® 80 mg/m2 IV, weekly for 12 weeks followed by 4 cycles of Epirubicin 90 mg/m2 IV and Cyclophosphamide 600 mg/m2 IV. Patients with HER-2 positive tumors also received HERCEPTIN® (Trastuzumab) and PERJETA® (Pertuzumab). The primary endpoint was pathologic Complete Response (pCR), defined as absence of microscopic residual invasive or noninvasive viable tumor cells in all resected specimens of the breast and axilla. This endpoint was chosen because pathologic Complete Response serves as a surrogate marker for long-term efficacy and outcomes. In this trial, the researchers noted a pathologic Complete Response rate of 38% with ABRAXANE® compared to 29% with TAXOL® (P<0.01). On subgroup analysis, this benefit was even more evident in patients with triple negative breast cancer (N=275), with a pCR rate of 48.2% in the ABRAXANE® group compared with 25.7% in the TAXOL® group (P <0.001). The incidence of peripheral neuropathy was higher in the ABRAXANE® group compared to TAXOL® group and this was attributed to higher weekly doses of ABRAXANE® administered. It is felt that a lower dose of weekly ABRAXANE® (100 mg/m2) would result in a decrease in the incidence of peripheral neuropathy, without compromising efficacy. The authors concluded that ABRAXANE® is superior to TAXOL® in early stage, high risk patients with breast cancer and this benefit is even more evident in those patients with triple negative disease, which comprises about 15% of all breast cancers. Untch M, Jackisch C, Schneeweiss A, et al. A randomized phase III trial comparing neoadjuvant chemotherapy with weekly nanoparticle-based paclitaxel with solvent-based paclitaxel followed by anthracyline/cyclophosphamide for patients with early breast cancer (GeparSepto); GBG 69. Paper presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, TX. Abstract S2-07.
Premature Ovarian Failure (POF) is a common unintended consequence of chemotherapy in premenopausal women. Besides of loss of fertility, which can influence treatment decisions in young women, ovarian failure can lead to menopausal symptoms, sexual dysfunction and loss of bone density. POEMS (Prevention of Early Menopause Study) is a randomized phase III trial designed to evaluate whether the addition of LHRH (Luteinizing Hormone-Releasing Hormone) analog Goserelin (ZOLADEX®), which suppresses the production of estrogens, to Cyclophosphamide based chemotherapy, would reduce POF in breast cancer patients, when compared to chemotherapy alone. Premenopausal patients less than 50 years of age, with hormone receptor negative (ER/PR negative ), Stage I-IIIA breast cancer, scheduled to receive chemotherapy, were randomly assigned to receive standard Cyclophosphamide based chemotherapy with or without monthly ZOLADEX® . Patients in the ZOLADEX® group received 3.6 mg SQ starting 1 week prior to the first dose of chemotherapy. The primary endpoint was ovarian failure at two years (defined as amenorrhea for the prior 6 months AND post-menopausal FSH level). Other endpoints included pregnancy and survival rates. The median age of the patients was 38 years and median follow up was 4.1 years. Of the 218 evaluable patients, 135 premenopausal women were evaluable for the primary end point. POF rates were 22% in the chemotherapy alone group and 8% in the ZOLADEX® group (P=0.04). When the definition of POF was more liberal to include EITHER amenorrhea or elevated FSH but not both, POF rates were 45% in the chemotherapy alone group and 20% in the ZOLADEX® group (P=0.006). Among the 218 evaluable patients, more women in the ZOLADEX® group achieved at least one pregnancy (21%) compared to 11% in the chemotherapy alone group (P=0.03). Secondary outcomes also favored the ZOLADEX® group with a Disease free Survival (DFS) rate of 78% in the chemotherapy alone group compared with 89% in the ZOLADEX® group (P=0.04) and Overall Survival (OS) rate of 82% in the chemotherapy alone group compared with 92% in the ZOLADEX® group (P=0.05). The authors concluded that the addition of ZOLADEX® to chemotherapy improved fertility prospects with a lower incidence of Premature Ovarian Failure and more pregnancies. Further, the improved Disease Free Survival and Overall Survival is an important additional perk and prevention of Premature Ovarian Failure with ZOLADEX® may be a consideration not only in premenopausal patients with hormone receptor positive breast cancer but also in other malignancies such as lymphomas, when treated with similar chemotherapeutic agents. Goserelin for Ovarian Protection during Breast-Cancer Adjuvant Chemotherapy. Moore HC, Unger JM, Phillips K, et al. N Engl J Med 2015; 372:923-932
PERJETA® (Pertuzumab) is a recombinant humanized monoclonal antibody that binds to the HER2 at a different epitope of the HER2 extracellular domain (subdomain II) compared to HERCEPTIN® and prevents the dimerization of HER2 with HER3 receptor. PERJETA® stimulates antibody-dependent, cell-mediated cytotoxicity similar to HERCEPTIN®. By combining HERCEPTIN® and PERJETA®, a more comprehensive blockade of HER2 signaling can be accomplished, as these two agents bind to different HER2 epitopes and may complement each other and improve efficacy, as was demonstrated in early phase trials. The CLEOPATRA trial is a phase III study in which 808 treatment naive HER positive metastatic breast cancer patients, were randomly assigned to receive either HERCEPTIN® plus Docetaxel or this two drug combination given along with PERJETA®. PERJETA® was given as an 840 mg loading dose followed by a 420 mg maintenance dose, HERCEPTIN® was given as an 8 mg/kg loading dose followed by a 6 mg/kg maintenance dose and Docetaxel was given at 75 mg/m2 for at least 6 cycles. Treatment was administered every 3 weeks and continued until disease progression. The primary end point of this study was Progression Free Survival and secondary end points included Overall Survival, Objective Response Rate and safety. A previous analysis performed in May 2012 showed that the addition of PERJETA® to the combination of HERCEPTIN® and Docetaxel significantly prolonged Progression Free Survival compared to HERCEPTIN® plus Docetaxel alone (18.5 months vs 12.4 months) but the median overall survival had not been reached then. In this final Overall Survival analysis, at a median follow up of 50 months, median Overall Survival was 56.5 months with the PERJETA® combination compared to 40.8 months in the non-PERJETA® group (hazard ratio [HR] = 0.68; P<0.001). This meant that adding PERJETA® to HERCEPTIN® and Docetaxel increased the median Overall Survival by 15.7 months. The increase in Progression Free Survival by 6.3 months with the PERJETA® combination, was again maintained (HR = 0.68, P < 0.0001), at the time of the final analysis. The median duration of response was 20.2 months with the PERJETA® combination compared to 12.5 months in the non-PERJETA® group. The incidence of symptomatic left ventricular dysfunction as well as declines in left ventricular ejection fraction, were rare and similar between the two treatment groups. Based on the CLEOPATRA study, women with HER positive metastatic breast cancer should be considered candidates, for treatment with a combination of PERJETA®, HERCEPTIN® and Docetaxel. Swain S, Baselga J, Kim S, et al. N Engl J Med 2015; 372:724-734
Cyclin Dependent Kinases (CDK) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. IBRANCE® is a reversible, oral, small molecule inhibitor of Cyclin Dependent Kinases (CDK) 4/6 and is the first CDK inhibitor approved by the FDA. This agent in pre-clinical studies was noted to reduce cellular proliferation of Estrogen Receptor positive Breast Cancer cell lines by blocking progression of cells from G1 into S phase of the cell cycle and was also noted to be synergistic with anti-estrogens. The approval of IBRANCE® was based on an open-label, randomized, multicenter, phase II study which included postmenopausal women with ER-positive, HER2-negative, advanced (locally advanced or metastatic) Breast Cancer who had not received previous systemic treatment for advanced disease. This trial enrolled and randomly assigned 165 patients, to receive either IBRANCE® 125 mg PO daily for 21 consecutive days, followed by 7 days off treatment) plus FEMARA® (2.5 mg PO daily continuously throughout the 28-day cycle (N=84) or FEMARA® alone (N=81). Among the 165 patients, 43% had received chemotherapy and 33% had received anti-hormonal therapy as a neoadjuvant or adjuvant treatment. Fortynine percent (49%) of patients had no prior systemic therapy in the neoadjuvant or adjuvant setting. The majority of patients (98%) had stage IV disease, 48% had visceral disease and 17% had bone only disease. The primary endpoint was investigator-assessed Progression Free Survival. The median PFS was 20.2 months in the IBRANCE® plus FEMARA® group and 10.2 months in the FEMARA® alone group (HR=0.488, P=0•0004). In patients with measurable disease, the Overall Response rate was higher in the IBRANCE® plus FEMARA® group compared to the FEMARA® alone group (55% versus 39%, P=0.04). The median duration of response for those who had a partial or complete response was 20.3 months with a combination of IBRANCE® plus FEMARA® vs 11.1 months with FEMARA® alone. The most common Grade 3–4 adverse events in the IBRANCE® plus FEMARA® group were neutropenia and leucopenia but without any cases of neutropenic fever. Unlike chemotherapy, the duration of neutropenia was brief with rapid recovery of blood counts. The authors concluded that the addition of IBRANCE® to FEMARA® significantly improved Progression Free Survival in women with advanced Estrogen Receptor positive and HER2-negative breast cancer. This combination may therefore be a reasonable treatment option in this patient group, soon after metastatic disease is diagnosed. Biomarkers expression (cyclinD1 amplification and/or loss of p16) had no impact on outcomes suggesting that the biomarker for IBRANCE® may be the Estrogen Receptor itself, rather than CDK4/6 kinases. Finn RS, Crown JP, Lang I, et al. Lancet Oncol 2015; 16:25-35
HERCEPTIN® binds to subdomain IV of the HER2 extracellular domain and blocks the downstream cell signaling pathways (PI3K-AKT pathway) and induces Antibody Dependent Cellular Cytotoxicity (ADCC). HERCEPTIN® in combination with chemotherapy has been proven to significantly improve Progression Free Survival and Overall Survival in patients with advanced breast cancer. Adjuvant chemotherapy in combination with HERCEPTIN® has been shown to reduce the relative risk of relapse by 52% and relative risk of death by 33%. The National Comprehensive Cancer Network (NCCN) has recommended adjuvant chemotherapy with HERCEPTIN® for patients with small, HER positive, node-negative tumors, including those with T1bN0 tumors, even though there are little or no data supporting this recommendation, because these patients are generally not included in adjuvant therapy studies. Further, the chemotherapy regimens often recommended (ACTH, TCH) along with HERCEPTIN® are relatively toxic. The authors in this study chose a less toxic chemotherapy regimen than the regimens often recommended for those patients with high risk disease. In this multicenter, investigator initiated study, 406 patients with tumors measuring up to 3 cm in greatest dimension received weekly treatment with TAXOL® (Paclitaxel) and HERCEPTIN (Trastuzumab) for 12 weeks, followed by 9 months of HERCEPTIN® monotherapy. Close to 50% of the patients had tumors 1 cm in diameter or less, about 40% of the patients had tumors 1-2 cm in diameter and majority of the tumors (56%) were high grade. Treatment regimen consisted of TAXOL® 80 mg/m2 IV weekly, for 12 weeks and HERCEPTIN® 4 mg/kg loading dose IV on day 1, followed by 2 mg/kg weekly, for a total of 12 doses followed by HERCEPTIN® 6 mg/kg every 3 weeks for an additional 40 weeks, for a total of 52 weeks of treatment with HERCEPTIN®. Patients who underwent lumpectomy received either partial breast radiation before the initiation of the therapy, or radiation of the whole breast, following completion of treatment with TAXOL®. Treatment with HERCEPTIN® was continued during the time patient was receiving radiation therapy. Adjuvant hormonal therapy was recommended for women with hormone-receptor positive tumors after the completion of TAXOL® treatment. The primary end point was survival free from invasive disease. The median follow up period was 4 years. The 3-year rate of survival free from invasive disease was 98.7%. Treatment was very well tolerated with a low incidence of heart failure (0.5%) and neuropathy. The authors concluded that a less toxic regimen such as HERCEPTIN® given along with weekly TAXOL® has significant efficacy, decreasing the risk of recurrence in this patient group, most notable during the first three years after diagnosis. They also point out that the risk of recurrence of breast cancer is greatest during the first 3-5 years after diagnosis and it would seem unlikely that a different chemotherapy regimen administered with HERCEPTIN® would impact the risk of late recurrences. Tolaney SM, Barry WT, Dang CT, et al. N Engl J Med 2015;372:134-141
The sentinel node is the first lymph node(s) to which cancer cells are most likely to metastasize from a primary tumor. With the introduction of intraoperative lymphatic mapping in the 1990s, Sentinel Lymph Node Biopsy (SLNB) has gained general acceptance and is the preferred procedure in appropriate circumstances. Unlike Axillary Lymph Node Dissection (ALND), SLNB is associated with a lower incidence of Lymphedema, seroma at the surgery site, paresthesias and restriction of joint movement. Nine randomized clinical trials have not shown any difference in mortality among patients who underwent ALND or SLNB for either lymph node metastases or negative sentinel lymph nodes, validating Sentinel Lymph Node Biopsy (SLNB). The American Society of Clinical Oncology (ASCO) first published guidelines on the use of SLNB for patients with early stage breast cancer in 2005, based on one randomized clinical trial. Since then, additional information from 9 randomized clinical trials and13 cohort studies pertinent to SLNB and ALND has resulted in this ASCO Clinical Practice Guideline Update.
PERJETA® (Pertuzumab) is a recombinant humanized monoclonal antibody that binds to the HER2 at a different epitope of the HER2 extracellular domain (subdomain II) compared to HERCEPTIN® and prevents the dimerization of HER2 with HER3 receptor. PERJETA® stimulates antibody-dependent, cell-mediated cytotoxicity similar to HERCEPTIN®. By combining HERCEPTIN® and PERJETA®, a more comprehensive blockade of HER2 signaling can be accomplished, as these two agents bind to different HER2 epitopes and may complement each other and improve efficacy, as was demonstrated in early phase trials. The CLEOPATRA trial is a phase III study in which 808 treatment naive HER positive metastatic breast cancer patients, were randomly assigned to receive either HERCEPTIN® plus Docetaxel or this two drug combination given along with PERJETA®. PERJETA® was given as an 840 mg loading dose followed by a 420 mg maintenance dose, HERCEPTIN® was given as an 8 mg/kg loading dose followed by a 6 mg/kg maintenance dose and Docetaxel was given at 75 mg/m2 for at least 6 cycles. Treatment was administered every 3 weeks and continued until disease progression. The primary end point of this study was Progression Free Survival and secondary end points included Overall Survival, objective response rate and safety. A previous analysis performed in May 2012 showed that the addition of PERJETA® to the combination of HERCEPTIN® and Docetaxel significantly prolonged Progression Free Survival compared to HERCEPTIN® plus Docetaxel alone (18.5 months vs 12.4 months) but the median overall survival had not been reached then. In this final Overall Survival analysis, at a median follow up of 50 months, median Overall Survival was 56.5 months with the PERJETA® combination compared to 40.8 months in the non-PERJETA® group (hazard ratio [HR] = 0.68; P=0.0002). This meant that adding PERJETA® to HERCEPTIN® and Docetaxel increased the median Overall Survival by 15.7 months. The increase in Progression Free Survival by 6.3 months with the PERJETA® combination, was again maintained (HR = 0.68, P < 0.0001) at the time of the final analysis. The incidence of symptomatic left ventricular dysfunction as well as declines in left ventricular ejection fraction, were rare and similar between the two treatment groups. Based on the CLEOPATRA study, women with HER positive metastatic breast cancer, should be considered candidates, for treatment with a combination of PERJETA®, HERCEPTIN® and Docetaxel. Swain S, Kim S, Cortes J, et al. Presented at: the 2014 Congress of the European Society of Medical Oncology; September 26-30, 2014; Madrid, Spain. Abstract 350O