Screening Mammography Starting at Age 40 years May Reduce Breast Cancer Deaths by 40 percent

In the US, about 33 million screening mammograms are performed each year. Currently, the major national health care organizations in the US have different recommendations for screening mammography which has led to some confusion and emotional counterarguments. These several different recommendations include 1) Annual screening at ages 40 to 84 years. 2) Annual screening at ages 45 to 54 years and then biennially at ages 55 to 79 years. 3) Biennial screening at ages 50 to 74 years.

In a recently published study (CANCER,  August 21, 2017), it was noted  that the greatest breast cancer-specific mortality reduction was achieved with annual screening of women starting at age 40 years, saving 29,369 lives from breast cancer. This is the first study to compare the three most widely discussed recommendations for screening mammography, head to head.

First CAR T-Cell Immunotherapy Approved by the FDA for Acute Lymphoblastic Leukemia

The FDA on August 30, 2017, granted regular approval to KYMRIAH® (Tisagenlecleucel) for the treatment of patients up to age 25 years with B-cell precursor Acute Lymphoblastic Leukemia (ALL), that is refractory or in second or later relapse. KYMRIAH® is the first Chimeric Antigen Receptor (CAR) T-cell immunotherapy approved by the FDA. A single infusion of KYMRIAH® was highly efficacious, in patients with relapsed and refractory ALL, and was associated with a high and durable Remission Rate. This technology may be applied to other malignancies, as new antigen targets are identified.

Antibiotics May Impair the Efficacy of Immune Checkpoint Inhibitors

SUMMARY: The American Cancer Society estimates that about 63,990 new cases of kidney cancer will be diagnosed in the United States in 2017 and about 14,400 patients will die from this disease. The understanding of the Immune checkpoints has lead to the development of novel immunotherapies. Immune checkpoints or gate keepers are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells may be related to their ability to escape immune surveillance, by inhibiting T lymphocyte activation. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies have been developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as PD-1(Programmed cell Death-1), etc. Following inhibition of PD-1 by specific antibodies, T cells are unleashed, resulting in T cell proliferation and activation with subsequent therapeutic responses.

Preclinical studies have suggested that immune-based therapies for cancer may have a very complex interplay with the host’s microbiome and there may be a relationship between gut bacteria and immune response to cancer. Broad-spectrum antibiotics can alter the bacterial composition and bacterial diversity of our gut, by killing the good bacteria. It has been postulated that this may negate the benefits of immunotherapy and influence treatment outcomes. Previously published studies have shown that intestinal microbiota modulates the anticancer immune effects of YERVOY® (Ipilimumab), an Immune checkpoint inhibitor.

The authors in this publication evaluated the effect of broad-spectrum antibiotic use, in patients with metastatic Renal Cell Carcinoma (mRCC), treated with Immune checkpoint inhibitors. In this study, 80 mRCC patients treated in prospective trials with checkpoint inhibitors were enrolled. These patients had received anti-PD-1/PD-L1 monotherapy, primarily Nivolumab (N=67), a combination of a PD-1 inhibitor and a CTLA-4 inhibitor such as Ipilimumab (N=10), and a combination of anti-PD-L1 therapy and Bevacizumab (N=3). A majority of the patients (65%) were male, 88% had mRCC with clear cell histology, and 80% of the patients had prior nephrectomy. Using IMDC (International Metastatic Renal Cell Carcinoma Database Consortium) criteria, 21% had favorable risk disease, 57% had intermediate risk and 22% had poor risk disease. Sixteen patients (20%) had been treated with broad-spectrum antibiotics, mostly Beta-lactamases or Fluoroquinolones, for up to 1 month prior to starting treatment with immunotherapy. A retrospective analysis was conducted and the Progression Free Survival (PFS), Objective Response Rate (ORR), and Overall Survival (OS), in the group that received broad-spectrum antibiotics, were compared with the group that did not receive broad-spectrum antibiotics.

It was noted that the PFS was four-fold higher in patients who did not receive antibiotics compared to those who received antibiotics (8.1 months vs 2.3 months, P<0.001) and this was statistically significant. This benefit was maintained after adjusting for age, gender, IMDC risk groups, tumor burden and proton pump inhibitors. Additionally, the ORR was higher in those who did not receive antibiotics compared to those who were treated with antibiotics (P<0.002). At a median follow up of less than 6 months, there was already a negative trend in Overall Survival, driven by broad-spectrum antibiotic usage.

It was concluded that in this first analysis, broad-spectrum antibiotics had a negative impact on outcomes, among patients with metastatic Renal Cell Carcinoma, treated with Immune checkpoint inhibitors. Caution should therefore be exercised when prescribing antibiotics to this patient group, so that the efficacy of immunotherapy is not compromised. These concerns may be true across different tumor types and additional follow up is underway. Impact of antibiotics on outcome in patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors. Derosa L, Routy B, Enot D, et al. J Clin Oncol 35, 2017 (suppl 6S; abstract 462)

First CAR T-Cell Immunotherapy Approved by the FDA for Acute Lymphoblastic Leukemia

SUMMARY: The FDA on August 30, 2017, granted regular approval to KYMRIAH® (Tisagenlecleucel) for the treatment of patients up to age 25 years with B-cell precursor Acute Lymphoblastic Leukemia (ALL), that is refractory or in second or later relapse. KYMRIAH® is the first Chimeric Antigen Receptor (CAR) T-cell immunotherapy approved by the FDA.

What is (CAR) T-cell immunotherapy? Chimeric Antigen Receptor (CAR) T-cell therapy is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure, and genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR). These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen on tumor cells. These genetically engineered and reprogrammed CAR T-cells are grown in the lab and are then infused into the patient. These cells in turn proliferate in the patient’s body and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen. KYMRIAH® (genetically engineered T-cells) seeks out cancer cells expressing the antigen CD19, which is found uniquely on B cells and destroy them. Patients, following treatment with CAR T-cells, develop B-cell aplasia (absence of CD19 positive cells) due to B-cell destruction and may need immunoglobin replacement. Hence, B-cell aplasia can be a useful therapeutic marker, as continued B-cell aplasia has been seen in all patients who had sustained remission, following CAR T-cell therapy. Cytokine Release Syndrome, an inflammatory process is the most common and serious side effect of CAR T-cell therapy and is associated with marked elevation of Interleukin-6. Cytokine release is important for T-cell activation and can result in high fevers and myalgias. This is usually self limiting although if severe can be associated with hypotension and respiratory insufficiency. Tocilizumab (ACTEMRA®), an Interleukin-6 receptor blocking antibody produces a rapid improvement in symptoms. This is however not recommended unless the symptoms are severe and life threatening, as blunting the cytokine response can in turn negate T-cell proliferation. Elevated serum Ferritin and C-reactive protein levels are surrogate markers for severe Cytokine Release Syndrome.

The CAR T-cells have been shown to also access sanctuary sites such as the central nervous system and eradicate cancer cells. CD19 antigen is expressed by majority of the B cell malignancies and therefore most studies using CAR T-cell therapy have focused on the treatment of advanced B-cell malignancies such as Chronic Lymphocytic Leukemia (CLL), Acute Lymphoblastic Leukemia (ALL) and Non Hodgkin lymphoma (NHL), such as Diffuse Large B-Cell Lymphoma (DLBCL). Previously published studies have shown significant responses with CAR T-cell therapy in patients with relapsed and refractory B-cell ALL. But the durability of remission has remained unclear.

This FDA approval was based on ELIANA, an ongoing single-arm, open-label, multicenter, global, phase II study, that has enrolled 88 pediatric/young adult patients with CD19-positive Relapsed/Refractory B-cell ALL and with 5% or more bone marrow lymphoblasts by morphology. The median age was 12 years, 59% of patients had prior allogeneic Stem Cell Transplant and patients had received a median of 3 lines of therapy previously. Following completion of lymphodepleting chemotherapy which in most patients consisted of Fludarabine/Cyclophosphamide, patients were infused with a single dose of KYMRIAH® within 2 to 14 days following the completion of lymphodepleting chemotherapy. The primary endpoint was Overall Remission Rate – Complete Remission [CR] + CR with incomplete blood count recovery [CRi], within 3 months. Secondary endpoints included Duration of Remission (DOR), Overall Survival, Safety, and cellular kinetics.

The authors reported an updated interim analysis with a median study follow up of 6.4 months. Of the 63 patients who were evaluable for efficacy, the Overall Remission Rate was 83%, with 63% of patients achieving a Complete Remission (CR) and 19% achieving a Complete Remission with incomplete hematological recovery (CRi) within 3 months of KYMRIAH® infusion. All patients with a confirmed CR or CRi were Minimal Residual Disease (MRD) negative by flow cytometry. The relapse-free probability at 6 months after remission onset was 75% and the median Duration of Remission has not been reached. The probability of survival at 6 months was 89% and at 12 months was 79%. Thirteen percent (13%) of responders went on to have allogeneic Stem Cell Transplant within 6 months, while in remission.

The most common adverse reactions were Cytokine Release Syndrome (CRS), hypogammaglobulinemia, nausea, diarrhea, vomiting, fever, infections, headache, encephalopathy, hypotension, bleeding episodes, tachycardia, hypoxia and fatigue. Grade 3 or 4 adverse events were noted in 84% of patients. Patients with Severe Cytokine Release Syndrome were effectively treated with the Interleukin-6 receptor blocking antibody Tocilizumab (ACTEMRA®). The expansion of the genetically engineered T-cells in vivo correlated with CRS severity, and persistence of these reprogrammed T cells along with B-cell aplasia in peripheral blood was observed for 1 year or more in some responders.

The authors concluded that the ELIANA trial is the first multicenter trial of a CAR T-cell therapy and a single infusion of KYMRIAH® was highly efficacious, in patients with relapsed and refractory ALL, and was associated with a high and durable remission rate. This technology may be applied to other malignancies, as new antigen targets are identified. Buechner J, Grupp SA, Maude SL, et al. Global registration trial of efficacy and safety of CTL019 in pediatric and young adult patients with relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL): update to the interim analysis. Presented at: 2017 EHA Congress; June 22-25, 2017; Madrid, Spain. Abstract S476.

Late Breaking Abstract – ASCO 2017 Single Dose Radiation Therapy as Effective as Multiple Fractions for Metastatic Spinal Cord Compression

SUMMARY: Metastatic Spinal Cord Compression (MSCC) first described by Spiller in 1925, is an oncologic emergency and is a well recognized complication of cancer. Approximately 10% of all patients with cancer develop metastatic disease to the spinal column. Even though any solid tumor can metastasize to the spine, more than 50% of MSCC cases are caused by breast cancer, prostate cancer and lung cancer. The risk of MSCC is particularly high in those patients with widespread malignancy and those with known spinal metastases. Pathological compression fracture of the vertebral body or direct tumor invasion can cause compression of the spinal cord or cauda equina resulting in irreversible neurological deficit as well as paraplegia. Common symptoms include back pain, tingling, numbness and difficulty walking. Early recognition of symptoms and prompt intervention is therefore imperative to prevent neurological damage.

Patients with MSCC, in addition to steroids, are often treated with Radiation Therapy (RT) to relieve pain and improve neurological function and mobility. There is however no standard Radiation Therapy schedule. ASTRO (American Society for Radiation Oncology) in its “Choosing Wisely” guidelines recommended not using extended fractionated schemes (more than 10 fractions) for palliation of bone metastases. Equivalent pain relief can be accomplished following 30 Gy in 10 fractions, 20 Gy in 5 fractions, or a single 8 Gy fraction. It was also recommended that strong consideration should be given to a single 8 Gy fraction, for patients with a limited prognosis or with transportation difficulties.

SCORAD III is a randomized phase III study which evaluated whether a single-dose Radiation Therapy (RT) was as effective as multifraction RT administered over 5 days, without compromising patient outcomes. Enrolled patients (N=688) were randomized 1:1 to receive External Beam spinal canal RT as a single dose of 8 Gy (N=345) or 20 Gy in 5 fractions (N=343). Eligible patients had spinal cord or cauda equina (C1-S2) compression, confirmed by MRI/CT scan, treatable within a single radiation field, with no prior RT to the same area and had a life expectancy of more than 8 weeks. The median age was 70 years, 73% were male and 44% had metastatic prostate, 18% had metastatic lung, 11% had metastatic breast and another 11% had metastatic GastroIntestinal cancers. Patients were stratified by Ambulatory Status (AS), site of primary, and presence or absence of non-skeletal metastases. The primary endpoint of the study was Ambulatory Status, measured on a four-point scaleGrade 1: Able to walk normally, Grade 2: Able to walk with a walking aid (such as a cane or walker), Grade 3: Has difficulty walking even with walking aids and Grade 4: Dependent on wheelchair. Two third of the patients (66%) were ambulatory with or without walking aids (Ambulatory Status of 1 to 2) at study entry.

It was noted that at 8 weeks, 69.5% of patients who received single-dose radiation therapy and 73.3% of those who received five doses had an Ambulatory Status of 1 to 2 and could walk normally or with a walking aid such as a cane or a walker, suggesting that both single dose and longer course radiation treatments helped patients with their mobility. The median Overall Survival was similar in the two treatment groups – 12.4 weeks with a single dose versus 13.7 weeks with five doses, and this was not statistically significant (HR=1.02; P=0.81). The proportion of patients experiencing severe side effects was similar in the two treatment groups (20.6% vs 20.4%), but mild side effects were less common in the single dose of 8 Gy group compared to those receiving multiple fractions (51% vs 56.9%).

The authors concluded that a single radiation dose of 8 Gy in patients with metastatic Spinal Cord Compression was non-inferior and was as effective as longer course multiple fractions, for Ambulatory Status at 8 weeks, as well as Overall Survival. They added that this would mean fewer hospital visits and more time with the family, at least for patients with a short life expectancy. It should however be noted that in this study, at the time of enrollment, majority of patients were fully ambulatory or were able to walk with a walking aid. Whether single dose radiation therapy is adequate for those patients with very advanced involvement of the spine, however remains to be seen. SCORAD III: Randomized non-inferiority phase III trial of single dose radiotherapy (RT) compared to multifraction RT in patients (pts) with metastatic spinal canal compression (SCC). Hoskin P, Misra V, Hopkins K, et al. J Clin Oncol. 35;2017 (suppl; abstr LBA10004).

Study Finds Dramatic Increase in ColoRectal Cancer Incidence among Young Adults

SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 135,430 new cases of ColoRectal Cancer will be diagnosed in the United States in 2017 and over 50,260 patients are expected to die of the disease. The lifetime risk of developing ColoRectal Cancer is about 1 in 20 (5%).

Even though the incidence of Colorectal cancer (CRC) in the United States has been rapidly declining overall, primarily driven by screening, the incidence however has been increasing among adults younger than age 50 years. To understand this trend, the authors in this publication conducted a retrospective cohort study among 490,305 patients aged 20 years and older, who were diagnosed with colorectal cancer between 1974 and 2013, using data from nine oldest Surveillance, Epidemiology, and End Results (SEER) registries. The SEER program is considered the gold standard for cancer registration worldwide because of the high quality of data and is the only source for historical population-based cancer incidence in the United States. This study included people born in 1890 thru 1990. Colorectal cancer incidence trends were analyzed by 5-year age group and birth cohorts.

The authors noted variations in CRC incidence patterns by age, tumor location in the colon, calendar period, and birth cohort. The study found that in adults aged 20-39 years, after a decrease in the previous decade, colon cancer incidence rates increased by 1.0-2.4% per year since the mid-1980s thru 2013. For adults aged 40-54 years during the same period, colon cancer incidence rates increased by 0.5-1.3%. Conversely, from the mid-1980s thru 2013, colon cancer rates declined in adults aged 55 years and older. In adults younger than age 50 years, there was an increasing trend for tumors to be confined to the distal colon, with the exception of adults aged 40-49 years, among whom there was an also an increasing trend for proximal tumors.

The incidence of rectal cancer has been increasing even longer and faster than colon cancer, rising about 3.2% per year from 1974-2013 in adults aged 20-29 years and from 1980-2013 in adults aged 30-39 years. In adults aged 40 to 54, rectal cancer rates increased by 2.3% per year from the 1990s to 2013. Again, rectal cancer rates declined, in adults aged 55 years and older, from 1974-2013.

Compared with adults born around 1950, those born around 1990 had double the risk of colon cancer and quadruple the risk of rectal cancer. The increase in the incidence of CRC in young adults has been attributed to western style, high carbohydrate, high fat, low fiber diet which can initiate inflammation and proliferation in the colonic mucosa within two weeks. Other lifestyle factors associated with CRC include obesity, high consumption of processed meat and alcohol, low levels of physical activity and cigarette smoking. Further, young patients are 58% more likely than older patients to be diagnosed with advanced versus localized stage CRC, due to delayed follow-up of symptoms, sometimes for years and these young adults are less likely to be screened for colon cancer, despite their symptoms.

The authors concluded that there is an increasing rate of colon and rectal cancer among young and middle-aged adults in the US and compared with adults born around 1950 when the risk was at the lowest, those born around 1990 have double the risk of colon cancer and quadruple the risk of rectal cancer. They added that as nearly a third of rectal cancer patients are younger than age 55 years, screening initiation before age 50 years should be considered. Colorectal Cancer Incidence Patterns in the United States, 1974-2013. Siegel RL, Fedewa SA, Anderson WF, et al. J Natl Cancer Inst. 2017 Aug 1;109(8). doi: 10.1093/jnci/djw322.