Tag: 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.

Parenteral therapy with bisphosphonates in patients with skeletal metastases has significantly decreased the risk of skeletal related events and need for radiation therapy. Evolving data suggests that bisphosphonates in general and one of the more commonly used bisphosphonates Zoledronic acid (Zometa) has been shown to induce apoptosis, inhibit angiogensis, inhibit tumor metastases and exhibit synergy with certain anticancer agents in early stage Breast Cancer.

In the Z-FAST and ZO-FAST trials, Zoledronic acid improved disease free survival in hormone receptor positive early stage breast cancer. This intriguing data regarding the benefits of bisphosphonates in early stage breast cancer is likely to move this class of agents into the adjuvant setting, to become a part of adjuvant therapy.

This MammaPrint technology is capable of predicting the risk of recurrence of breast cancer, in patients with node negative, stage I and II invasive breast cancer whose tumors are 5cm or less in size regardless of the hormone receptor and menopausal status. This FDA approved test uses microarray analysis and looks at 70 critical genes capable of predicting prognosis and classifies patients into low risk (10% chance of recurrence in 10 years without any adjuvant therapy) or high risk (29% chance of recurrence in 10 years without any adjuvant therapy). It can further subclassify breast cancer using molecular subtyping into Luminal type, Basal type and ERBB2 (HER-2) subtypes.

This technology differs from Oncotype DX assay in that fresh tissue specimen is required for testing, hormone receptor status and menopausal state are not relevant and patients are classified into low risk and high risk categories without an intermediate risk group. Decisive treatment recommendations can therefore be made.

This testing methodology has been extensively validated and will help us decide who would and who would not benefit from chemotherapy. With the ability to sub type breast cancer based on molecular profiling and the benefits demonstrated with PARP (Poly (ADP-ribose) polymerase inhibitors in the triple negative (Basal type) breast cancer patients, the era of personalized medicine is welcome news for patients with breast cancer. There is also promising data demonstrating the benefit of this test in predicting disease outcome in patients with 1-3 positive lymph nodes as well as its ability to predict response following neoadjuvant chemotherapy in breast cancer.

Using DNA microarray analysis breast tumors can be divided into 5 subtypes:
1) Luminal A: Tumor cells originate from luminal epithelium and have high levels of ER expression, express cytokeratin (CK) 8 and 18, are low grade, are less responsive to chemotherapy and have a good prognosis
2) Luminal B: Similar to Luminal A with a different gene expression profile. Prognosis in this subtype is slightly worse than in Luminal A.
3) Basal-like: Express markers of basal or myoepithelial cells CK 5/6, CK 8/18, vimentin, smooth muscle actin and EGFR. Tumors are ER, PR and HER negative (Triple negative). P53 mutations are common in this subtype. Tumors tend to be aggressive and this subtype includes BRCA-1 mutant tumors. This is a heterogenous group and only 70% of triple negative breast tumors fall into this subtype.
4) HER-2 amplified: Tumors have amplificated HER gene located on the long arm of chromosome 17 and are usually ER and PR negative but have upregulation of vascular endothelial growth factor (VEGF). The aggressive behavior of these tumors has been tempered with the availability of trastuzumab.
5) Normal breast-like: Tumors have gene expression profile similar to normal breast epithelium and prognosis is similar to Luminal B subtype

This molecular classification may help us better understand the biology of breast tumors and thus develop and plan therapy accordingly

Fulvestrant is a selective estrogen receptor downregulator administered as an injection once a month. Approved in April 2002 by the FDA for the treatment of hormone receptor positive metastatic breast cancer, the recommended dose was Faslodex 250 mg given intramuscularly once a month. FDA has now recommended a new dosing schedule based on the CONFIRM (Comparison of Faslodex in Recurrent or Metastatic Breast Cancer) trial, in which the new dosing schedule significantly prolonged progression free survival compared to the originally recommended dose. The new dosing schedule is as follows – Faslodex 500 mg given intramuscularly on days 1,15 and 29 and monthly thereafter.

The results of the Women’s Health Initiative (WHI) trial which began in 1993, was updated after a 11 year followup. The outcomes from this study should give us pause as we consider postmenopausal hormonal therapy. The conclusions of this study published in JAMA are clear. Estrogen plus Progestin in postmenopausal women not only increases the risk of breast cancer but also results in more advanced cancer at the time of diagnosis. Further there is an increased rate of breast cancer death in this population. Whether short term use of hormonal treatment in postmenopausal individuals to alleviate symptoms is safe, remains unknown and it may be wise not to consider hormonal treatment in these individuals.