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Recent Developments in Breast Cancer Show Survival Increase

Charles Bankhead, Senior Editor, MedPage Today

Patients with advanced hormone receptor (HR)-positive breast cancer obtained a first-ever survival improvement with a targeted agent as ribociclib (Kisqali) plus endocrine therapy led to a 24% absolute improvement over endocrine therapy alone.

Estimated 42-month survival rose from 46% with placebo to 70.2% with the CDK4/6 inhibitor. The difference represented a 29% reduction in the mortality hazard for the ribociclib group, Sara Hurvitz, MD, of the University of California Los Angeles, reported at the American Society of Clinical Oncology (ASCO) meeting.

"This is the first study to demonstrate improved survival for a targeted therapy," she said. "We saw no new safety signals. ... Women feel well while on this therapy, they can raise their children, work on their career, be functional, and feel good while they are receiving therapy that we have now shown extends how long they will live."

The findings from the randomized, placebo-controlled phase III MONALEESA-7 add to a previously reported progression-free survival benefit with ribociclib plus endocrine therapy in the form of goserelin and either a nonsteroidal aromatase inhibitor or tamoxifen. The trial involved 672 premenopausal women with advanced HR-positive/HER2-negative breast cancer and no prior endocrine therapy for advanced disease. All patients received endocrine therapy and were randomized to ribociclib or placebo.

The survival improvement with ribociclib also followed a report from the 2018 European Society for Medical Oncology congress showing a 7-month improvement in survival in patients with advanced HR-positive breast cancer treated with palbociclib (Ibrance) and fulvestrant (Faslodex). A subgroup analysis revealed a statistically significant 10-month improvement in median overall survival (OS) in patients who previously responded to endocrine therapy.

Immunotherapy's Case for Bigger Role in Breast Cancer

After a relatively slow start in breast cancer versus other types of tumors, immunotherapy has now demonstrated therapeutic potential in the condition.

Results of the IMpassion130 trial led directly to FDA approval of a chemotherapy-atezolizumab (Tecentriq) combination for untreated metastatic triple-negative breast cancer (TNBC). Clinical investigation has expanded into other settings.

A trial of neoadjuvant durvalumab (Imfinzi) and chemotherapy in newly diagnosed TNBC led to improved pathologic complete response (pCR), as compared with chemotherapy alone, particularly among patients who received the PD-L1 inhibitor as a single agent before starting combination therapy. The results were consistent with the KEYNOTE-522 trial that demonstrated significant improvement in the pCR rate with the addition of pembrolizumab (Keytruda) to chemotherapy for newly diagnosed TNBC.

"We've learned that using these drugs earlier in the course of metastatic disease is likely to be more effective," said Leisha Emens, MD, of the University of Pittsburgh Hillman Cancer Center. "I think we have a lot to learn about how to convert 'cold' tumors to 'hot' tumors, but a number of studies are exploring combinations to identify a rational way to do that. We have to think about how the immune system is primed and what we need to do to induce T-cells and cause a tumor to respond. All in all, though, I think we've made a lot of progress."

PFS Doubled with AKT Inhibitor Plus Endocrine Therapy

Women with metastatic hormone receptor-positive breast cancer lived more than twice as long without disease progression when they received the investigational AKT inhibitor capivasertib in addition to fulvestrant (Faslodex), a randomized phase II study showed.

Median progression-free survival (PFS) increased from 4.8 months with fulvestrant alone to 10.3 months with the combination. Patients with and without PIK3CA activating mutations benefited from the combination, as reported at ASCO.

"I can't explain it," Sacha Jon Howell, MD, of the Christie NHS Foundation Trust in Manchester, England, said of the duality of the benefit. "It's not really what we were expecting. There's preclinical data to show that there is a preferential benefit in cell lines, for example, with the altered pathway."

The objective response rate also increased with the combination (41% vs 12%), as did the clinical benefit rate (55% vs 36%). A preliminary analysis of OS demonstrated a "strong trend" in favor of the capivasertib arm (26 vs 20 months, P=0.071).

Male Breast Cancer: Uncommon But Deadly

Delayed diagnosis and inadequate treatment received much of the blame for a higher breast cancer mortality among men, who account for about 1% of all new breast cancer cases.

An analysis of data for 16,000 men and 1.8 million women with breast cancer showed an adjusted overall mortality risk 19% higher among men. The disparity persisted across all breast cancer stages and remained significantly lower among men at 3 years (86.4% vs 91.7%, P<0.001) and 5 years (77.6% vs 86.4%, P<0.001), as OS (45.8% vs 60.4%). The disparity could not be explained solely by men's generally higher mortality rate as compared with women, Xiao-Ou Shu, MD, PhD, of Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, and colleagues reported in JAMA Oncology.

In all, clinical characteristics of male patients and inadequate treatment accounted for 63.3% of excess mortality.

"I believe that these disparities may largely reflect differences in therapeutic strategies and medication adherence that in part result from the inadequacy of randomized controlled trial data to demonstrate benefit in men," said Kathryn Ruddy, MD, of the Mayo Clinic in Rochester, Minnesota, who was not involved in the study.

"Our treatments for breast cancer and our lifestyle recommendations, including the importance of exercise and minimization of alcohol after treatment, have greatly improved over the past few decades, leading to reductions in mortality," Ruddy added. "But men are not experiencing all of these advances, likely due to uncertainties about how to apply data from female breast cancer trials to men."

Chemotherapy Dose Still Matters

Both OS and PFS suffered when patients did not receive at least 85% of the planned cumulative dose of adjuvant chemotherapy, a retrospective review of 1,300 women showed.

Hazard ratios for OS and PFS increased by about 50% when treatment failed to achieve the threshold cumulative dose. The findings added to a body of literature dating back about 25 years, when a landmark study identified the 85% total cumulative doses as optimal for first- and second-generation chemotherapy regimens. The new study updated results to incorporate contemporary chemotherapy regimens and, in the process, confirmed the clinical importance of the 85% threshold, as reported in the Journal of the National Comprehensive Cancer Network.

"What surprised us the most was how dramatically early reductions in chemotherapy affect survival compared to later modifications," first author Zachary Veitch, MD, of the University of Toronto, said in a statement. "This became even more apparent when patients were further separated based on chemotherapy dose cutoffs. Often the first cycle of chemotherapy can be difficult for patients, and oncologists must convey the need for maintaining initial dose intensity, while using other medications to control side effects and manage comorbidities."

The analysis included 1,302 women with newly diagnosed, HER2-negative early breast, treated during 2007 to 2014. Most of the patients (1,100) received at least 85% of the total planned dose of adjuvant chemotherapy. The 202 patients who received <85% of the planned cumulative dose had a 5-year disease-free survival rate of 79.2% vs 85.9%, representing a 45% increase in the hazard ratio (P=0.040) and 5-year OS of 80.7% vs 88.8%, a 50% increase in the hazard versus patients who met the 85% chemotherapy threshold (P=0.043).

More Fuel for the Mammography Debate

Average-risk women should have a baseline breast cancer risk assessment at age 25 and begin annual mammographic screening at 40, according to new risk-based breast cancer screening recommendations adopted by the American Society of Breast Surgeons (ASBrS).

The guidelines represent a break from the U.S. Preventive Services Task Force (USPSTF) and the American Cancer Society (ACS), which recommend annual screening of average-risk women starting at 50 and 45, respectively. The USPSTF and ACS recommendations noted the potential harms of false-positive results and cited evidence that a majority of positive screening mammography results turn out to be false.

In a statement released at its annual meeting, the ASBrS acknowledged "known disadvantages" of mammography for women ages 40 to 45 and stated that women should be informed of potential downsides.

"The ASBrS position statement advocates for annual screening mammography beginning at age 40 years, because we have chosen to prioritize the life-saving benefits of screening mammography," said Lisa Newman, MD, of NewYork Presbyterian/Weill Cornell Medicine in New York City, and chair of the ASBrS guideline committee. "Furthermore, as physicians that guide patients through decisions regarding management of breast cancer on a daily basis, we have unique perspectives regarding the value of early detection and its impact on surgical as well as systemic and radio-therapeutic options."

In addition to recommending annual screening at 40, the ASBrS recommends supplemental imaging for women at increased risk because of dense breast tissue. Women at increased risk due to hereditary susceptibility genes or prior radiation to the chest wall should have a breast MRI at 25 and begin annual mammography at 30. Annual screening mammography should begin at 35 for women with a strong family history or increased predicted lifetime risk by a validated risk-assessment model.

Breast tomosynthesis (or 3D mammography) is the preferred form of mammography in all screening scenarios outlined by the ASBrS.

LAST UPDATED 09.23.2019

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