News Study Shows: Annual Breast Cancer Screening Beginning at Age 40 Reduces Mastectomy Risk

Having a yearly mammogram greatly reduces the risk of mastectomy following breast cancer in women between the ages of 40 and 50, according to a study being presented today at the annual meeting of the Radiological Society of North America (November 28 - December 3, 2010, McCormick Place, Chicago).

"The results of this study support the importance of regular screening in the 40 to 50 age group," said lead author Nicholas M. Perry, M.B.B.S., F.R.C.S., F.R.C.R., director of The London Breast Institute at The Princess Grace Hospital in London. "Women in this age group who had undergone mammography the previous year had a mastectomy rate of less than half that of the others."

An estimated 207,090 new cases of invasive breast cancer will be diagnosed in American women in 2010. Currently, the American Cancer Society recommends annual mammography screening for women beginning at age 40 in the U.S., but last year, the U.S. Preventive Services Task Force recommended changing the guidelines to begin screening biennially (every other year) at age 50. There are no routine screening guidelines for women under 50 in the U.K.

The researchers studied the benefits of screening women between the ages of 40 and 50, the frequency of mammography and the type of treatment after breast cancer diagnosis.

Dr. Perry and colleagues reviewed the clinical data available on women from 40 to 50 that had been diagnosed with breast cancer and treated at The London Breast Institute. Between 2003 and 2009, 971 women had been diagnosed with breast cancer. At the time of diagnosis, 393 (40%) of the women were under 50, with 156 of these women completing treatment at the center. Of the treated women, 114 (73%) had no prior mammograms. Forty-two women had been previously screened with mammography, of whom 29 had at least one mammogram within the previous two years. Of those, 16 women had a mammogram one year prior.

"We reviewed the records of the women needing mastectomy to determine whether or not they had undergone mammography the previous year," Dr. Perry said. "We were surprised at the degree of benefit obtained from yearly screening in this age group."

Data showed that mastectomy was the required treatment for 3 (19%) of the 16 women who had been screened the prior year, compared to 64 (46%) of the 140 women who had not been screened in the past year.

"Regular screening is already proven to lower the chance of women dying from breast cancer," Dr. Perry said. "The results of our study support the importance of regular screening in the under-50 age group and confirm that annual mammography improves the chances of breast conservation should breast cancer develop."

Dr. Perry's coauthors for this article are Sue Milner, B.Sc., D.C.R., Kefah Mokbel, M.B.B.S., M.S., F.R.C.S., Stephen W. Duffy, B.Sc., M.Sc., and Katja Pinker, M.D.

For more information
Prior Mammography in Women Aged 40-50 at a UK Center in Accordance with ACS Guidelines Lowers Mastectomy Rate Following Breast Cancer (Abstract)

This article was first published online at Onco'Zine - The International Cancer Network

DM1, an Investigational Antibody-Drug Conjugate, Shows Encouraging Results in Women With Highly Advanced HER2-positive Breast Cancer

Results of a Phase II study of trastuzumab (Herceptin®, Genentech) in combination with DM1 (T-DM1), an investigational HER2 antibody-drug conjugate being developed by Genentech, in collaboration with Roche and Immunogen, Inc., shows encouraging results in women with highly advanced HER2-positive breast cancer.

Positive Phase I and Phase II findings were first reported at the 2007 [1] and 2008 [2], respectively, annual meetings of the American Society of Clinical Oncology (ASCO) with T-DM1 in patients with HER2-positive (HER2+) metastatic breast cancer (MBC) that progressed on treatment with trastuzumab. In the Phase II study, 60% of patients also had been treated with lapatinib (Tykerb®, GlaxoSmithKline).

As assessed by independent review, the T-DM1 combination shrank the tumors (also known as objective response) in 33% of women with advanced (metastatic) HER2-positive breast cancer that had worsened following previous treatment.

Women in this study had already received an average of seven drugs for metastatic disease, including chemotherapy, trastuzumab and lapatinib, prior to receiving T-DM1. No new or unexpected safety signals were observed. The results were presented today at the 32nd Annual CTRC-AACR San Antonio Breast Cancer Symposium (SABCS) from 9 to 13 December 2009 (Abstract #710). [3]

Antibody-drug conjugates or ADCs [4] are a unique combination of a precise and targeted monoclonal antibody, a stable linker, and a potent cytotoxic. They have broad utility in basic, preclinical, and clinical applications. [5] T-DM1 combines two approaches in one medicine: the anti-cancer activity of the trastuzumab antibody, which blocks signals that make the cancer more aggressive and signals the body’s immune system to destroy the cancerous cells, and the targeted delivery of the potent cytotoxic DM1.

“Breast cancer is the most common cancer among women worldwide with more than one million new cases diagnosed every year and nearly 400,000 deaths, so it is vital that we continue to provide more treatment options” said William M. Burns, CEO of Roche Pharma.

According to the American Cancer Society [6], breast cancer is the second leading cause of cancer death in the United States. Women diagnosed with advanced (metastatic) disease have a poor prognosis and only 27% survive five years.

Approximately 15 to 30% of breast cancers are HER2-positive. [7] When HER2-positive breast cancer is advanced, the disease has spread to other parts of the body, most commonly to the lungs, bones, liver and brain. At this stage of the disease, the current goals of existing treatments include symptom relief, tumor shrinkage, improved quality of life and increasing the amount of time women with advanced breast cancer live without the cancer worsening. There are no treatment guidelines or FDA-approved treatment options for women with advanced HER2-positive breast cancer if the disease progresses following treatment with trastuzumab and lapatinib.

“The much anticipated data on the investigational drug T-DM1 will be welcomed by physicians treating women with early and very advanced stages of breast cancer as it will offer them more choices for fighting this devastating disease,” Burns noted.

"Despite major advances in HER2-positive breast cancer, the disease may still progress after multiple treatments, to the point where there are no approved HER2-targeted medicines," said Hal Barron, M.D., executive vice president, Global Development and chief medical officer, Genentech. "Results from this study are promising for women who need new treatment options, and we will discuss next steps of the T-DM1 development program with the FDA."

"These results are significant because they demonstrate that T-DM1 was effective at shrinking tumors in women whose cancer had progressed following prior treatment with standard therapies for HER2-positive breast cancer," said Ian Krop, M.D., Ph.D., a medical oncologist at Dana-Farber Cancer Institute, and lead investigator on the study.

In this single-arm study, 45% of women experienced a clinical benefit (defined as a complete or partial tumor response, or stable disease, maintained for at least six months), as assessed by independent review. Adverse events were similar to those observed in previous clinical trials of T-DM1. The most common severe adverse events included thrombocytopenia (a low level of platelets in the blood, 5.5%) and back pain (3.6%), and the most common adverse events were fatigue (59.1%) and nausea (37.3%). No severe (Grade 3 or higher) cardiac-specific side effects were observed. One patient with pre-existing, non-alcoholic fatty liver disease died with hepatic failure.

Ongoing clinical trials
The new treatment options is currently in trial in a Phase II study, known as TDM4374g, a single-arm, multi-center trial designed to assess T-DM1 as a single agent in 110 women with HER2-positive advanced breast cancer whose disease had progressed after receiving at least two prior HER2-targeted treatments (trastuzumab and lapatinib) in the metastatic setting, as well as an anthracycline, a taxane, and capecitabine. [8]

The primary endpoint of this study is objective response rate (a complete or partial tumor shrinkage of at least 30%, determined by two tumor assessments at least 28 days apart), as measured by an independent review facility. Secondary endpoints include safety, clinical benefit rate, duration of response and progression-free survival (PFS). Duration of response and PFS data are not yet mature and will be presented at a future meeting.

The results of the data presented during the SABCS follow on from results from another phase II study (TDM4258) presented at ASCO 2009 which also showed encouraging results in women with advanced HER2-positive breast cancer [9, 10].

For more information:
[1] Beeram M, Krop I, Modi S, Tolcher A, Rabbee N, et al A phase I study of trastuzumab-MCC-DM1 (T-DM1), a first-in-class HER2 antibody-drug conjugate (ADC), in patients (pts) with HER2+ metastatic breast cancer (BC). Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 1042.
[2] Beeram M, Burris III, HA, Modi S, Birkner M, Girish S, et al. A phase I study of trastuzumab-DM1 (T-DM1), a first-in-class HER2 antibody-drug conjugate (ADC), in patients (pts) with advanced HER2+ breast cancer (BC). J Clin Oncol 26: 2008 (May 20 suppl; abstr 1028).
[3] Krop I, LoRusso P, Miller KD, Modi S, Yardley D, et al. A Phase II Study of Trastuzumab-DM1 (T-DM1), a Novel HER2 Antibody-Drug Conjugate, in Patients Previously Treated with Lapatinib, Trastuzumab, and Chemotherapy. SABCS Poster Session 5: Treatment: Her2-Targeted Therapy (Date/Time: Saturday, December 12, 2009; 5:30 PM-7:30 PM)
[4] Teicher BA. Antibody-drug conjugate targets. Curr Cancer Drug Targets. 2009 Dec;9(8):982-1004
[5] Hofer T, Skeffington LR, Chapman CM, Rader C. Molecularly defined antibody conjugation through a selenocysteine interface. Biochemistry. 2009 Dec 22;48(50):12047-57.
[6] American Cancer Society. Breast Cancer Facts & Figures 2009-2010. Atlanta: American Cancer Society, Inc.
[7] Murphy CG, Modi S. HER2 breast cancer therapies: a review. Biologics. 2009;3:289-301. Epub 2009 Jul 13.
[8] A Study of of Trastuzumab-Mcc-DM1 Administered Intravenously to Patients With HER2-Positive Metastatic Breast Cancer.
[9] A Study of Trastuzumab-MCC-DM1 Administered Intravenously to Patients With HER2-Positive Metastatic Breast Cancer.
[10] Vogel CL, Burris HA, Limentani S, Borson R, O'Shaughnessy J, et al. A phase II study of trastuzumab-DM1 (T-DM1), a HER2 antibody-drug conjugate (ADC), in patients (pts) with HER2+ metastatic breast cancer (MBC): Final results. J Clin Oncol 27:15s, 2009 (suppl; abstr 1017).

Also:
Onco’Zine – The International Cancer Network

Advisory Committee Recommends Randomized Trial to Support Proposed Indication for Clofarabine in Adult AML

The FDA’s Oncologic Drugs Advisory Committee voted 9 to 3 that a randomized, controlled trial is needed to support the currently proposed label expansion for clofarabine (Clolar® , Genzyme) in adult myeloid leukemia (AML). Clofarabine is currently approved as the standard of care for pediatric acute lymphoblastic leukemia (ALL) patients who have relapsed or have refractory disease after at least two prior regimens. The drug has an Orphan Drug designation.

The committee found that the single-arm clinical study results submitted to support the label expansion showed clofarabine was an active agent in acute AML patients, but concluded that a randomized clinical trial should be necessary to better interpret clofarabine’s efficacy and safety in the proposed patient population.

“I am happy that the three panel members who have significant experience in treating older adults with AML recognized the value of clofarabine in these patients and did not see the need for a randomized trial,” said Harry P. Erba, M.D., Ph.D., University of Michigan, one of the co-principal investigators of the CLASSIC II study.

“The panel indicated that it wasn’t an easy decision to vote for a randomized trial as Clolar was clearly active in these patients,” said Mark Enyedy, president of Genzyme Oncology and Multiple Sclerosis. “The requirement for a randomized control trial as a standard of evidence was a major focus of the discussion. We remain committed to the clinical development of Clolar in this patient population with high unmet medical need.”

Genzyme is conducting a randomized Phase 3 trial comparing clofarabine in combination with cytarabine to cytarabine alone in relapsed and refractory adult AML patients 55 years old or older. The trial continues to exceed patient accrual expectations, and results are expected in 2011. Clofarabine is also being investigated in clinical trials by most of the leading AML experts and major cooperative leukemia investigation groups in the United States and Europe.

The CLASSIC II study, discussed at the Oncologic Drugs Advisory Committee (ODAC), analyzed 112 adult AML patients aged 60 years and older with one or more unfavorable prognostic factors, including age 70 years or older, an antecedent hematologic disorder (AHD), poor performance status, or intermediate or unfavorable cytogenetics. As reported in peer-reviewed literature, and discussed by a separate panel of AML experts who recommended the trial, these risk factors predict poor outcomes in older patients with conventional induction therapy.

Patients in the trial had a 45.5 percent overall remission rate, including a 37.5 percent complete remission (CR) rate, and remission rates were consistent regardless of the type or number of unfavorable risk factors. The study also found that clofarabine remissions were durable. Durable CR is accepted as an established surrogate for clinical benefit in patients with acute leukemias. The median duration of remission in overall responders (CR+CR with incomplete platelet recovery) was estimated as 52 weeks (12 months). Most patients who responded to treatment achieved remission after one cycle.

The safety profile of clofarabine in the Phase 2 study was generally predictable and manageable. The all-cause induction 30-day mortality was 9.8 percent and was consistent regardless of the presence or number of unfavorable prognostic factors. The safety findings were consistent with those for the approved clofarabine pediatric ALL indication. The most commonly occurring adverse reactions included nausea, vomiting, diarrhea, febrile neutropenia, rash, headache, fever, fatigue, hypokalemia, pneumonia, anorexia, pruritus, increased liver transaminases, neutropenia, thrombocytopenia, mucosal inflammation.

The American Cancer Society estimates that approximately 12,810 people will be diagnosed with AML in the United States in 2009. About 70 percent of these patients will die from the disease, and almost all will be adults. The median age of a patient with AML is about 67 years. As an acute disease, AML progresses rapidly and is typically fatal within weeks or months if left untreated.