Tag: Breast Cancer

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.

BCIRG OO6 – Adjuvant TCH for Breast Cancer presented at the SABCS 2009 by Slamon, D et al. is ready for review.

In summary, here are the findings:

The authors concluded that the addition of trastuzumab to either an anthracycline or non-anthracycline based chemotherapy regimens provides similar and significant benefit both in terms of disease free survival and overall survival and this benefit is seen in both low and high risk patients .

To view the entire Synopsis and Clinical Relevance, log on to https://www.oncoprescribe.com – if aren’t registered yet; the subscription is free.

Timing of Trastuzumab administration when given along with chemotherapy in an adjuvant setting, is gaining more clarity. Updated information presented at the 2009 San Antonio Breast Cancer Symposium suggests that, as was administered in group C of the N9831 trial, Trastuzumab started concurrently with taxane resulted in a better outcome, with improvement in Disease Free Survival compared to sequentially administering Trastuzumab following completion of taxane chemotherapy. This should clearly be more appealing to patients, as the duration of adjuvant parenteral therapy would be shortened by approximately 3 months in addition to the decrease in the risk of disease recurrence.

An updated analysis of the phase III EGF 104900 trial demonstrated some interesting findings. Combining Trastuzumab with Lapatinib – dual HER blockade, in patients with metastatic breast cancer who had progressed on anthracyclines, taxanes and trastuzumab, improved overall survival without significant adverse events. This is in spite of a 50% cross over from the control group to the dual HER blockade group. This may be a telling tale of how individuals with advanced metastatic breast cancer can benefit with targeted therapy.

Should we be in a hurry to abandon anthracyclines due to cardiotoxicity concerns? Think again. Weigh the risk benefits. More to come.