The scary stuff!!!

[Jackie07]

[Abstract]

Risk factors for late relapse and death in patients with early breast cancer.

C GK, M B, B Z.
Adjuvant treatments reduce the risk for recurrence and death from breast cancer; but even 10-15 years after diagnosis, these risks persist. The aim of our study was to identify prognostic factors for relapse and death in the second decade after primary surgery. Patients with early breast cancer treated from 1983-1987 (n=1035) were included. Patients' characteristics, tumor prognostic factors, treatments, data on recurrence and death were obtained from patients' charts and our cancer registry. Median follow-up was 17 (1-23) years. At 10 years after surgery, 515 (49.8%) patients were alive and of them 432 (41.7%) were relapse-free. Of the 432 patients being alive and relapse-free at 10 years 153 (35.4%) had an event thereafter, of them 38 (25%, 9% of all) had a relapse of breast cancer. For this period only the presence of lymphovascular invasion (LVI) and positive estrogen receptors (ER) were found as independent unfavorable prognostic factors for relapse-free (HR 2.09, p=0.007; HR 1.50, p=0.021, respectively) and overall survival (HR 2.15, p=0.006; HR 1.41, p=0.05, respectively) while tumor size, grade and nodal status had no prognostic significance. Positive ER and LVI are independent prognostic factors for relapse and death in the second decade after surgery in patients with early breast cancer. Key words: breast cancer, estrogen receptors, late relapse, lymphovascular invasion

[Jackie07]

Overview of resistance to systemic therapy in patients with breast cancer.

Gonzalez-Angulo AM, Morales-Vasquez F, Hortobagyi GN.
Department of Breast Medical Oncology, Unit 424, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030, USA.
Breast cancer is the most common cancer and the second leading cause of cancer death in American women. It was the second most common cancer in the world in 2002, with more than 1 million new cases. Despite advances in early detection and the understanding of the molecular bases of breast cancer biology, about 30% of patients with early-stage breast cancer have recurrent disease. To offer more effective and less toxic treatment, selecting therapies requires considering the patient and the clinical and molecular characteristics of the tumor. Systemic treatment of breast cancer includes cytotoxic, hormonal, and immunotherapeutic agents. These medications are used in the adjuvant, neoadjuvant, and metastatic settings. In general, systemic agents are active at the beginning of therapy in 90% of primary breast cancers and 50% of metastases. However, after a variable period of time, progression occurs. At that point, resistance to therapy is not only common but expected. Herein we review general mechanisms of drug resistance, including multidrug resistance by P-glycoprotein and the multidrug resistance protein family in association with specific agents and their metabolism, emergence of refractory tumors associated with multiple resistance mechanisms, and resistance factors unique to host-tumor-drug interactions. Important anticancer agents specific to breast cancer are described. Breast cancer is the most common type of cancer and the second leading cause of cancer death in American women. In 2002, 209,995 new cases of breast cancer were registered, and 42,913 patients died of it. In 5 years, the annual prevalence of breast cancer will reach 968,731 cases in the United States. World wide, the problem is just as significant, as breast cancer is the most frequent cancer after nonmelanoma skin cancer, with more than 1 million new cases in 2002 and an expected annual prevalence of more than 4.4 million in 5 years. Breast cancer treatment currently requires the joint efforts of a multidisciplinary team. The alternatives for treatment are constantly expanding. With the use of new effective chemotherapy, hormone therapy, and biological agents and with information regarding more effective ways to integrate systemic therapy, surgery, and radiation therapy, elaborating an appropriate treatment plan is becoming more complex. Developing such a plan should be based on knowledge of the benefits and potential acute and late toxic effects of each of the therapy regimens. Despite advances in early detection and understanding of the molecular bases of breast cancer biology, approximately 30% of all patients with early-stage breast cancer have recurrent disease, which is metastatic in most cases. The rates of local and systemic recurrence vary within different series, but in general, distant recurrences are dominant, strengthening the hypothesis that breast cancer is a systemic disease from presentation. On the other hand, local recurrence may signal a posterior systemic relapse in a considerable number of patients within 2 to 5 years after completion of treatment. To offer better treatment with increased efficacy and low toxicity, selecting therapies based on the patient and the clinical and molecular characteristics of the tumor is necessary. Consideration of these factors should be incorporated in clinical practice after appropriate validation studies are performed to avoid confounding results, making them true prognostic and predictive factors. A prognostic factor is a measurable clinical or biological characteristic associated with a disease-free or overall survival period in the absence of adjuvant therapy, whereas a predictive factor is any measurable characteristic associated with a response or lack [cont'd on next posting]

[Jackie07]

lack of a response to a specific treatment. The main prognostic factors associated with breast cancer are the number of lymph nodes involved, tumor size, histological grade, and hormone receptor status, the first two of which are the basis for the AJCC staging system. The sixth edition of the American Joint Committee on Cancer staging system allows better prediction of prognosis by stage. However, after determining the stage, histological grade, and hormone receptor status, the tumor can behave in an unexpected manner, and the prognosis can vary. Other prognostic and predictive factors have been studied in an effort to explain this phenomenon, some of which are more relevant than others: HER-2/neu gene amplification and protein expression, expression of other members of the epithelial growth factor receptor family, S phase fraction, DNA ploidy, p53 gene mutations, cyclin E, p27 dysregulation, the presence of tumor cells in the circulation or bone marrow, and perineural and lymphovascular space invasion. Systemic treatment of breast cancer includes the use of cytotoxic, hormonal, and immunotherapeutic agents. All of these agents are used in the adjuvant, neoadjuvant, and metastatic setting. Adjuvant systemic therapy is used in patients after they undergo primary surgical resection of their breast tumor and axillary nodes and who have a significant risk of systemic recurrence. Multiple studies have demonstrated that adjuvant therapy for early-stage breast cancer produces a 23% or greater improvement in disease-free survival and a 15% or greater increase in overall survival rates. Recommendations for the use of adjuvant therapy are based on the individual patient's risk and the balance between absolute benefit and toxicity. Anthracycline-based regimens are preferred, and the addition of taxanes increases the survival rate in patients with lymph node-positive disease. Adjuvant hormone therapy accounts for almost two thirds of the benefit of adjuvant therapy overall in patients with hormone-receptor-positive breast cancer. Tamoxifen is considered the standard of care in premenopausal patients. In comparison, the aromatase inhibitor anastrozole has been proven to be superior to tamoxifen in postmenopausal patients with early-stage breast cancer. The adjuvant use of monoclonal antibodies and targeted therapies other than hormone therapy is being studied. Interestingly, some patients have an early recurrence even though they have a tumor with good prognostic features and at a favorable stage. These recurrences have been explained by the existence of certain cellular characteristics at the molecular level that make the tumor cells resistant to therapy. Selection of resistant cell clones of micrometastatic disease has also been proposed as an explanation for these events. Neoadjuvant systemic therapy, which is the standard of care for patients with locally advanced and inflammatory breast cancer, is becoming more popular. It reduces the tumor volume, thus increasing the possibility of breast conservation, and at the same time allows identification of in vivo tumor sensitivity to different agents. The pathological response to neoadj uvant systemic therapy in the breast and lymph nodes correlates with patient survival. Use of this treatment modality produces survival rates identical to those obtained with the standard adjuvant approach. The rates of pathological complete response (pCR) to neoadjuvant systemic therapy vary according to the regimen used, ranging from 6% to 15% with anthracycline-based regimens to almost 30% with the addition of a noncross-resistant agent such as a taxane. In one study, the addition of neoadjuvant trastuzumab in patients with HER-2-positive breast tumors increased the pCR rate to 65%. Primary hormone therapy has also been used in the neoadjuvant systemic setting. Although the pCR rates with this therapy are low, it significantly increases breast conservation. Currently, neoadjuvant systemic therapy is an important tool in not only assessing tumor response to an agent but also studying the mechanisms of action of the agent and its effects at the cellular level. However, no tumor response is observed in some cases despite the use of appropriate therapy. The tumor continues growing during treatment in such cases, a phenomenon called primary resistance to therapy. The use of palliative systemic therapy for metastatic breast cancer is challenging. Five percent of newly diagnosed cases of breast cancer are metastatic, and 30% of treated patients have a systemic recurrence. Once metastatic disease develops, the possibility of a cure is very limited or practically nonexistent. In this heterogeneous group of patients, the 5-year survival rate is 20%, and the median survival duration varies from 12 to 24 months. In this setting, breast cancer has multiple clinical presentations, and the therapy for it should be chosen according to the patient's tumor characteristics, previous treatment, and performance status with the goal of improving survival without compromising quality of life. Treatment resistance is most commonly seen in such patients. They initially may have a response to different agents, but the responses are not sustained, and, in general, the rates of response to subsequent agents are lower. Table 1 summarizes metastatic breast cancer response rates to single-agent systemic therapy.
PMID: 17993229 [PubMed - indexed for MEDLINE]

[Jackie07]

Please note the pCR rate has increased to 65% with Herceptin. The statistics we see these days includes most patients who did not receive Herceptin. With Herceptin, Her-2 positive have become the most treatable breast cancer. We have become the lucky ones.

But just like all the advertisement would say, past performance is no guarantee and individual result may vary...

[StephN]

Hi -
Goops, being stage IV and NED for over 6 years now, I also wonder what the stats are for STAYING NED under the new drug treatments.

The nurses at my cancer center tell me that there are several women there like myself, as well as many who are stage IV active disease and fighting well.

I only know personally two others like myself who have remained NED for a long period. Althought there are a few on this site like Christine, Andi and a couple of others.

They must be still collecting current information from trial studies for stage IV. I know I am followed after being on a trial.

[mts]

This post only exemplifies how so much is known yet how little we understand cancer...

One more reason to make cancer a national priority that our elected officials have to bring to the level of attention equal to global warming... we all know that.

maria

[Vi Schorpp]

and thanks for bringing this up PinkGirl.

From Jackie's information, ....the presence of lymphovascular invasion (LVI) and positive estrogen receptors (ER) were found as independent unfavorable prognostic factors for relapse-free (HR 2.09, p=0.007; HR 1.50, p=0.021, respectively) and overall survival (HR 2.15, p=0.006; HR 1.41, p=0.05, respectively) while tumor size, grade and nodal status had no prognostic significance...

that's interesting because I had LVI and positive ER, and had no Herceptin. For those who had Herceptin, it appears to be more favorable.

[dlaxague]

Vi said: From Jackie's information, ....the presence of lymphovascular invasion (LVI) and positive estrogen receptors (ER) were found as independent unfavorable prognostic factors for relapse-free (HR 2.09, p=0.007; HR 1.50, p=0.021, respectively) and overall survival (HR 2.15, p=0.006; HR 1.41, p=0.05, respectively) while tumor size, grade and nodal status had no prognostic significance...

that's interesting because I had LVI and positive ER, and had no Herceptin. For those who had Herceptin, it appears to be more favorable.

Vi, the above is talking specifically about LATE relapse, after 10 years of no recurrence. The factors that increase risk for late relapse are not necessarily the same as the ones that increase risk for early relapse and early relapse is more common. Note that in the above article, they started with 1038 women diagnosed with primary cancer and based the ending stats that you reference on 38 women who recurred after 10 years. Not a very big number. Less than 4% (I am not strong in math). Plus, they are saying that "early treatment" (ie: chemo and I assume Herceptin) has no effect on late recurrence. 'Still trying to get my head around that one but this was discussed recently in another thread and made sense when I read the explanation.

Anyway, just wanted to make sure you saw the distinction between risk for "regular" recurrence within the first 10 years, when risk is highest for all of us, and "late" recurrence or relapse, when there are fewer women recurring but the risk factors affecting that have changed a bit.

Sorry no time right now to find that thread. Does anyone else remember what it was called?

Debbie Laxague