Risk of Recurrence in Early Breast Cancer
Clinical management of patients with early breast cancer is determined on an individual basis, taking into account many factors, including the risk of cancer recurrence. The clinical management of breast cancer is directly linked to pathological assessment of the cancer so accurate pathological interpretation of the breast cancer specimen is vital.
Common factors have been identified for predicting risk of recurrence in patients with breast cancer. They include:
Lymph Node Involvement
- Whether the tumor has spread to the lymph nodes at the time of diagnosis (node-positive) and, importantly, the number of lymph nodes in which cancer has been found.
- Factor in determining the stage of breast cancer
- Grade is a calculation based on how abnormal the cancer cells look under a microscope and how fast they are growing. There are 3 features when determining a cancer's grade: (1) the rate of cell division, (2) percentage of cancer composed of tubular structures, and (3) change in cell size and uniformity. If a tumor has been determined to be Grade 3 then there is a higher risk of recurrence than if the tumor was determined to be Grade 1.
HER2/neu (a growth-promoting protein) Status
- Gene that helps the growth of cells, how they, divide, and repair themselves. Positive or negative HER2/neu is important in the control of abnormal or defective cells that could become cancerous and might have implications for treatment. 15
Lymphatic Vessel Invasion (LVI)
- When pathologists look directly at the cancer under a microscope they determine whether cancer cells are found in the lymphatic vessels within the cancer itself.
Hormone Receptor Status:
- This status reflects whether the cancer is estrogen receptor positive (ER+) or not
(ER-) or progesterone receptor positive (PgR+) or not (PgR-). This status may have some prognostic information and, at this time, is used to plan treatment.
Health care professionals use these prognostic factors to help determine recommendations for appropriate adjuvant therapy and whether additional treatment should be considered after adjuvant therapy has been completed. 11,16,17
In 2005, the St. Gallen International Consensus Panel, a panel of experts in the field of early breast cancer, revisited risk categories for patients with ER/PgR-positive early breast cancer and determined that to qualify as "minimal-risk" [also called low-risk], all of the following criteria need to apply: cancer has not spread to the lymph nodes; tumor is <2 cm in greatest dimension; nuclei are small, with little increase or variation in size compared with breast epithelial cell nuclei, regular outlines, uniformity of nuclear chromatin; no cancer cells have invaded the blood or lymphatic vessels and cancer does not use the HER2neu pathway to grow
Better understanding of actual ongoing risk in all patients, including "low-risk" patient populations, is critical for optimizing treatment decisions. In this paper we will discuss some of the latest data that have emerged surrounding the risk women with early breast cancer face in terms of their disease returning.
Node-negative status at diagnosis has commonly been associated with a favorable patient outcome. However, long-term risk of recurrence and death are not well understood. Many current studies support the notion that there is a risk of recurrence for women with early breast cancer regardless of nodal status, estrogen receptor status, age, chemotherapy regimen, time on tamoxifen or time from initial diagnosis. 14
Many people have the misconception that after successful initial treatment, patients with early breast cancer who remain disease free for five years or more (according to existing tests) are unlikely to experience a recurrence of their cancer. However, recurrences can occur after five years.
In a meta-analysis (from seven different studies) of more than 3,500 patients who had received some type of post-surgical adjuvant therapy for breast cancer, risk of cancer recurrence was greatest during the first two years following surgery. After this period, the research showed a steady decrease in the risk of recurrence until year five when the risk of recurrence declined slowly and averaged 4.3% per year.18 But a substantial proportion of breast cancer recurrences seen in this study occurred more than five years after surgery, between years six and 12, even in patients who typically would be considered at low risk for recurrence because their cancer had not spread to the lymph nodes at the time of diagnosis (node-negative).18 What this research indicates is that through at least 12 years of follow-up, the risk of breast cancer recurrence remains appreciable and even some patients considered low risk have some risk of the cancer coming back.
Another meta-analysis, this one of nearly 37,000 women with early breast cancer, conducted by the Early Breast Cancer Trialists' Collaborative Group, found:
- Through the first 10 years after diagnosis, the cumulative incidence of recurrence and breast cancer-related deaths continued to increase, with a substantial portion of recurrences and breast-cancer related deaths occurring beyond five years after diagnosis.
- The recurrence rate among patients who did not receive adjuvant hormonal therapy was nearly 50% in node-positive patients and 32.4% in node-negative patients throughout the first 10 years after diagnosis. 9
These data showed that some years of adjuvant tamoxifen treatment substantially improved the 10-year survival of women with estrogen receptor-positive (ER+) tumors and of women whose tumors are of unknown ER status, even in women who had node-negative disease. 9
Another analysis of recurrence among ER+ patients found that use of tamoxifen therapy significantly improved patient outcomes in a population considered to be at minimal risk prior to this trial. However, even with adjuvant therapy, more than 20% of node-negative patients had their disease recur within 15 years after diagnosis. 11
Confirming these findings, a recent study showed that even for small tumors in the lowest risk category, the 10-year risk of breast cancer recurrence was as high as 12% in the absence of adjuvant therapy. Additionally in the absence of adjuvant therapy, even in the lowest risk category, the 10-year risk of breast cancer-related death is high, at 7%. 14
Another study showed that more than half of all breast cancer recurrences and two-thirds of all breast cancer deaths occur after completion of five years of standard tamoxifen therapy. 19
A study evaluating the risk of breast cancer recurrence following adjuvant therapy in 2,420 patients with early breast cancer showed that there was a substantial and continuing risk of recurrence long after completion of five years of standard adjuvant treatment. 20 Additionally, after the first five years, there were similar proportional rates of recurrence for node-negative and node-positive breast cancer patients. 20 Data from the National Surgical Adjuvant Breast and Bowel Project B-14 trial showed, however, that continued use of tamoxifen after five years was associated with an increase in serious adverse events, but no further efficacy benefits. 11
Many studies conducted in breast cancer reveal that most adjuvant therapies are essential tools in the fight against breast cancer as they decrease the risk of recurrence by at least one-third. But the ongoing risk of recurrence in patients with very small tumors and no nodal involvement points to the need to continue research into even greater improvements in ways to determine accurately a woman's risk of recurrence in order to evaluate the best treatment options available. Furthermore, it is essential that health care professionals communicate these findings with their patients while discussing treatment options.
As part of the treatment process, the risks and benefits of possible treatment options are necessarily discussed. In terms of the adjuvant therapy most commonly used, tamoxifen, the American Cancer Society indicated that tamoxifen can increase the risk of developing cancer of the lining of the uterus (endometrial cancer). This cancer is usually diagnosed at a very early stage and is generally curable by surgery. Tamoxifen can also increase the risk of uterine sarcoma, a rare cancer of the connective tissue of the uterus. Blood clots are another serious side effect of tamoxifen. Other side effects may include weight gain (although recent studies have not found this), hot flashes, vaginal discharge and mood swings. 21