Tag: Breast Cancer

SUMMARY: There is presently no clear consensus regarding breast cancer screening for women in their 40’s. The risk/benefit ratio of screening mammography has not been properly defined in this age group. In this review, Nelson and colleagues identified the risk factors for breast cancer and concluded that there is a 2 fold increase in the risk for breast cancer in women 40-49 years of age, who have dense breast tissue and first degree relatives with breast cancer. This meta analysis has identified a subset of patients in their 40’s who would benefit from screening mammography. Nelson HD, Zakher B, Cantor A, et al. Ann Intern Med. 2012;156:635-648

SUMMARY: The CLEOPATRA trial is a phase III trial in which 808 HER positive metastatic breast cancer patients, for their first line treatment, were randomized to either HERCEPTIN® plus Docetaxel or the above two drug combination given along with PERJETA® (Pertuzumab). PERJETA® is a recombinant humanized monoclonal antibody that binds to the HER2 dimerization domain and prevents the dimerization of HER2 with other HER receptors ie. HER3, HER1 and HER4. 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, P<0.001). This benefit was seen without increase in cardiotoxicity. It appears that PERJETA® complements HERCEPTIN® in targeting HER-2 receptor. Baselga J, Cortés J, Kim S, et al. N Engl J Med 2012; 366:109-119

In this Phase III trial involving first line treatment of patients with HER-2 positive metastatic breast cancer,  the addition of Pertuzumab (an anti-HER-2 humanized monoclonal antibody that inhibits receptor dimerization) to a combination of Trastuzumab and Docetaxel significantly prolonged progression-free survival, without increase in cardiotoxicity when compared to Trastuzumab and Docetaxel alone. It appears that Pertuzumab complements Trastuzumab in targeting HER-2 receptor.

These findings from the CLEOPATRA trial have demonstrated that comprehensive  HER-2 blockade may result in improved outcomes for patients with breast cancer  over expressing HER-2.

The original article was published in the January 2012  issue of the NEJM.

SUMMARY: Breast cancer is the second most common cause of death in the United States. Presently two Selective Estrogen Receptor Modulators (SERM’s), tamoxifen and raloxifene are approved by the FDA, for the primary prevention of breast cancer. Tamoxifen has been associated with increased risk of venous thromboembolism and endometrial cancers. Raloxifene can also be associated with venous thromboembolism but has not been associated with endometrial cancers. Exemestane is an irreversible, steroidal aromatase inactivator. This agent was evaluated in a randomized, placebo controlled, double blind study, to reduce the risk of invasive breast cancer in postmenopausal women, considered to be at moderately increased risk of developing breast cancer. Risk factors included age over 60 years, Gail five year risk score greater than 1.66% and prior atypical ductal/ lobular hyperplasia, LCIS, or DCIS with mastectomy. At a median follow up of 3 years, exemestane reduced the relative incidence of invasive breast cancers by 65% compared to placebo and this benefit was accomplished without serious toxicities and with minimal changes in quality of life. This is the first aromatase inhibitor/inactivator to demonstrate proven efficacy in breast cancer prevention, in a randomized clinical trial. N Engl J Med 2011; 364:2381-2391

Exemestane is an aromatase inactivator presently approved by the FDA for the treatment of breast cancer. This drug was studied in a large randomized clinical trial for the prevention of breast cancer. The results of this study were published in the June 23 issue of the NEJM. Exemestane reduced the relative incidence of invasive breast cancer by 65%, in postmenopausal women with moderate risk of developing breast cancer. The benefit with this drug was accomplished without any significant serious toxicities.

Breast Cancer is the second most common cause of cancer death in the United States. This new addition will be additional ammunition, in the fight against breast cancer

SUMMARY: Patients with triple negative breast cancer have inherent defects in several DNA repair pathways. These cancer cells therefore become increasing dependent on another DNA damage repair pathway called base excision repair (BER) pathway, for survival. It so happens that PARP 1(PolyAdenosine diphosphate Ribose Polymerase) is an important enzyme regulating the BER pathway. By inhibiting PARP1, the BER pathway is inhibited leading to extreme levels of DNA damage and eventual death of cancer cells. In an article published in the January, 2011 issue of the NEJM, the addition of a PARP inhibitor Iniparib to chemotherapy improved clinical benefit and survival of patients with advanced triple negative breast cancer. A phase II open label trial was conducted, in which 123 patients with metastatic triple negative breast cancer were randomly assigned to receive a combination of carboplatin and GEMZAR® (gemcitabine) with or without iniparib. Patients who received chemotherapy in combination with iniparib demonstrated improved rate of clinical benefit (partial or complete response plus stable disease for 6 or more months) from 34% to 56% (P=0.01). This was the primary end point. The addition of iniparib to chemotherapy also prolonged the median progression free survival from 3.6 months to 5.9 months (HR for progression, 0.59; P=0.01) and median overall survival from 7.7 months to 12.3 months (HR for death, 0.57; P=0.01). These gains were achieved without any significant increase in toxicities. This difficult to treat subtype of breast cancer may soon become extinct. N Engl J Med 2011; 364:205-214

SUMMARY: HALAVEN ® (Eribulin) is a non taxane inhibitor of microtubule dynamics and is a synthetic analog of halichondrin B, a product derived from a a sea sponge Halichodria okadai. It triggers apoptosis of cancer cells following prolonged mitotic inhibition. The EMBRACE trial is a randomized open label phase III study involving 762 heavily pretreated patients with locally recurrent or metastatic breast cancer. These patients must have had at least two prior chemotherapy regimens including taxanes and an anthracycline. Patients were randomized to either HALAVEN ® (508 patients) or to an approved treatment of their physician's choice and this could be single agent chemotherapy, hormonal therapy, biological therapy or palliative radiation therapy (254 patients). Nineteen percent of the patients had triple negative disease. There was a statistically significant improvement in overall survival in the HALAVEN ® group 13.1 months compared to 10.7 months in the control group. At one year, 54% of the patients were alive in the HALAVEN ® group compared to 44% in the control group. This statistically significant benefit was also seen in the overall response rates. We now have another agent with a distinct survival advantage for heavily pretreated metastatic breast cancer patients. J Clin Oncol 28:18s, 2010 (suppl; abstr CRA1004)

It used to be that patients with breast cancer requiring surgery had Radical Mastectomy until the 1970’s. It subsequently became clear that Modified Radical Mastectomy, a less aggressive surgical procedure was just as effective as Radical Mastectomy. The next major surgical advance in Breast Cancer was breast preservation with Lumpectomy, Axillary Lymph Node Dissection (ALND) and Radiation. This has been proven to be as good as Modified Radical Mastectomy. Because of the morbidity associated with complete ALND, the technique of Sentinel Lymph Node Dissection (SLND) was developed and it became clear that SLND by itself is as effective as ALND,  in early breast cancer, without the complications associated with ALND.

A randomized clinical trial results published in JAMA this month demonstrated that in women with invasive breast cancer and limited sentinel lymph node metastases, SLND was as effective as ALND. With this data, women diagnosed with breast cancer hopefully will not have to endure the morbidity associated with ALND which include swelling, pain, paresthesias and restriction of movement of the arm.

This philosophy of  ” more is not better” with regards to chemotherapy, held ground, after myeloablative therapy and transplantation for metastatic breast cancer patients showed no benefit. Hopefully newer “kinder and gentler” systemic agents will follow suit, just as the surgical techniques have evolved over the past 40 years.

Patients with triple negative breast cancer have inherent defects in several DNA repair pathways. These cancer cells therefore become increasing dependent on another DNA damage repair pathway called base excision repair (BER) pathway, for survival. It so happens that PARP 1(PolyAdenosine diphosphate Ribose Polymerase) is an important enzyme regulating the BER pathway.  By inhibiting PARP1, the BER pathway is inhibited leading to extreme levels of DNA damage and eventual death of cancer cells.

In an article published in the Jan 20,2011 issue of the NEJM, the addition of a PARP inhibitor Iniparib to a combination of Carboplatin and Gemzar in patients with metastatic triple negative breast cancer, resulted in superior Response Rates, median Progression Free Survival and Overall Survival. This difficult -to -treat subtype of breast cancer may soon become extinct.

Eribulin is a non taxane inhibitor of microtubule dynamics and is a synthetic analog of halichondrin B, a product derived from a a sea sponge Halichodria okadai. The EMBRACE trial is a randomized open label phase III study involving 762 heavily pretreated patients with locally recurrent or metastatic breast cancer. Patients were randomized to either Eribulin (508 patients) or to an approved treatment of their physician’s choice and this could be single agent chemotherapy, hormonal therapy, biological therapy or palliative radiation therapy (254 patients). There was a statistically significant improvement in overall survival in the Eribulin group 13.12 months compared to 10.65 months in the control group. This statistically significant benefit was also seen in the overall response rates.

We now have another agent with a distinct survival advantage for heavily pretreated metastatic breast cancer patients.