Development of Vaccines for High-Risk Ductal Carcinoma In situ of the Breast

With the widespread use of screening mammography, ductal carcinoma in situ (DCIS) has become the most frequently diagnosed cancerous lesion identified in the breast. Like invasive breast cancer, DCIS is heterogeneous and represents a relatively wide spectrum of diseases.

Low-grade DCIS either rarely develops into invasive disease or progresses slowly to invasiveness over the course of 8 to 10 years. On the other hand, if untreated, high-grade DCIS lesions that display comedonecrosis will likely develop into invasive breast cancers over a 5- to 7-year period. Following current conventional treatment with surgery with wide margins (lumpectomy; ref. 1), lumpectomy plus radiation therapy (2), or mastectomy, the overall prognosis for these patients is excellent. Nonetheless, many patients (at least 30%) require the more aggressive therapeutic option (mastectomy) either because of extensive disease or for fear of cancer recurrence.

The latter remains a significant risk, particularly in younger patients. Fortunately, the relatively long period of latency between the onset of DCIS and development of invasive breast cancer offers an opportunity for novel neoadjuvant interventions. The potential benefits of such neoadjuvant therapies include (a) reduction of risk for subsequent breast cancer, (b) reduction in the psychological effect of the disease related to fear of recurrence, and (c) reduction in the morbidity resulting from surgery and radiation.

The latter would be achieved through diminution in the extent of disease before the application of standard therapies, limiting the need for radiation and decreasing the need for extensive surgical
resections.

Breast Cancer Developments

Over-expression of the HER2/neu receptor occurs in 20 to 30 percent of breast tumors and is linked to poorer prognosis. The HER2/neu expression status determines whether or not patient will receive trastuzumab-based treatment. In clinical practice, over-expression of HER2/neu is routinely identified using Immunohistochemistry (IHC) or Fluorescence in Situ Hybridization (FISH), both of which are invasive approaches requiring tissue samples. Serum assays for the Extra Cellular Domain of HER2/neu receptor (HER2 ECD) have been reported but the use is very limited due to serum interference factors (e.g. human anti-animal immunoglobulin antibodies) that lead to false test results and inconsistency with tissue Her2 status. We have developed an ELISA based approach using an MBB buffer to eliminate false results and to obtain more accurate assessment of HER2 ECD levels. Using this refined assay we retroactively measured HER2/neu levels from breast cancer patients and controls. Abnormal HER2 ECD levels were detected in about 32% of invasive breast cancer patients but not in controls or patients with benign diseases. In addition, we also showed that patients with elevated serum HER2 levels appeared to have worse survival regardless of treatments. In a small group of 12 Ductal Carcinoma in situ (DCIS) patients who received HER2/neu peptide vaccination and surgery, only one patient showed constantly rising HER2 levels after treatment and this patient had recurrence of HER2 positive tumor within 5 years. Our studies indicate that once the serum interference issue is resolved, serum HER2 ECD can have potential clinical utility to supplement the tissue based tests.

Affiliation

Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, U.S.A.

Some Breast Cancer Facts

All Cancers

• In 2015, about 589,430 Americans are expected to die of cancer, or about 1,620 people per day. Cancer is the second most common cause of death in the US, exceeded only by heart disease, and accounts for nearly 1 of every 4 deaths.
   
• The 5-year relative survival rate for all cancers diagnosed in 2004-2010 was 68%, up from 49% in 1975-1977. This improvement in survival reflects both the earlier diagnosis of certain cancers and improvements in treatment.
   
• Cancer costs – The Agency for Healthcare Research and Quality (AHRQ) estimates that the direct medical costs (total of all health care expenditures) for cancer in the US in 2011 were $88.7 billion. Half of this cost is for hospital outpatient or office-based provider visits, 35% is inpatient hospital stays, and 11% is prescription medications.

Breast Cancer Specifically

• About 1 in 8 (12%) women in the US will develop invasive breast cancer over the course of her lifetime.
   
• For women in the U.S., breast cancer death rates are higher than those for any other cancer, besides lung cancer.
   
• About 2,350 new cases of invasive breast cancer are expected to be diagnosed in men in 2015. A man’s lifetime risk of breast cancer is about 1 in 1,000.
   
• About 40,290 women in the U.S. are expected to die in 2015 from breast cancer, though death rates have been decreasing since 1989. Women under 50 have experienced larger decreases. These decreases are thought to be the result of treatment advances, earlier detection through screening, and increased awareness.
   
• In 2015, there are more than 2.8 million women with a history of breast cancer in the U.S. This includes women currently being treated and women who have finished treatment.
   
• Besides skin cancer, breast cancer is the most commonly diagnosed cancer among American women. In 2015, it’s estimated that just under 30% of newly diagnosed cancers in women will be breast cancers.