Pinpointing pain: Is it cancer or cancer treatment?

Using Precision Diagnostics For Early Detection Of Lung Cancer

A key focus of R&D for Sanmed Biotech is precisely detecting and profiling lung nodules as a means to better diagnose lung cancer.Credit: Kateryna Kon/Science Photo Library/Getty

Lung cancer is the second most common type of cancer and the leading cause of cancer deaths worldwide. Early-stage lung cancer is often asymptomatic, meaning patients are typically diagnosed at an advanced stage, where tumours are growing rapidly and the prognosis is grave. A cross-disciplinary team at Sanmed Biotech, a precision medicine innovation firm founded in 2016, is hoping to improve the outlook for lung cancer through new solutions for early diagnosis.

"The survival rate of stage 1A lung cancer at 10 years is over 90%. Yet for late-stage lung cancer patients, the survival drops significantly and only the 5-year survival rate is calculated," says Frank Shi, CEO of Sanmed Biotech. "Early diagnosis of lung cancer is critical in reducing the mortality rate and prolonging survival."

Credit: Sanmed Biotech

Credit: Sanmed Biotech

Credit: Sanmed Biotech

As Shi explains, the company has its roots in Cynvenio Biosystems, a global pioneer in liquid biopsy technology founded in 2008 by Nobel-winning physicist and chemist, Alan J. Heeger, and company Zhuhai Livzon Diagnostics, one of China's first in vitro diagnostic products manufacturing enterprises.

Differentiating cancerous nodules

The research and development priority at Sanmed Biotech is to precisely detect and profile lung nodules — small lumps of tissue that can be benign, precancerous or metastatic tumours. Low dose computed tomography (LDCT) screening is the recommended test to detect and measure nodules, but it's fraught with challenges.

"Where nodules are found to be 15 or even 20 millimeters, clinicians may propose further testing, such as a positron emission tomography scan, bronchoscopy or tissue biopsy," says Xin Ye, product development director of Sanmed Biotech. "However, LDCT has proven difficult to accurately profile smaller suspect nodules, presenting a major diagnostic challenge for clinicians to determine whether the nodule is malignant or benign, or whether an invasive biopsy or immediate surgical resection is necessary."

An effective, non-invasive, early detection test is needed to improve the diagnostic efficacy of LDCT, and Sanmed Biotech's proprietary liquid biopsy technology, fits the bill, says Ye.

Sanmed's liquid biopsy assay uses a novel multiplex fluorescence in-situ hybridization (FISH) test to detect chromosomal aberrant cells (CACs) in peripheral blood: a technique developed in 2010 by Ruth Katz. In 2020, refinements of this technique by Katz's team led to improved diagnosis of benign and malignant lung nodules by detecting chromosomal abnormalities in the peripheral blood genome through a simple, safe, effective, non-invasive test.

Sanmed's test contrasts with other liquid biopsy technologies that detect 'antigen-dependent' circulating tumour cells (CTC): these may lose sensitivity if the tumour cells alter the antigen profile by leaking into the bloodstream. Sanmed's liquid biopsy assay can distinguish between benign and malignant lung nodules by identifying individual cells bearing gains and/or loss of specific chromosomal loci that are labeled with distinct fluorophores.

Towards greater diagnostic certainty

Early lung cancer diagnosis is also impeded by the absence of standardized methods for interpreting LDCT images. Due to imaging anomalies and human error, doctors may reach different diagnostic conclusions on the same scan. So, Sanmed Biotech has invested globally in specialized high-throughput computation and image recognition algorithms to automate the LDCT image and data analysis.

One outcome is the SANMED Target Call Lung Nodule Analysis Platform, which is built on deep convolutional neural networks and machine learning algorithms trained on a massive dataset of around 300,000 annotated pulmonary nodules. This platform can automatically reconstruct, segment, and analyse the LDCT images and label the lung nodules with the relevant parameter values indicating malignancy risks.

In 2022, Sanmed Biotech published its preliminary findings in Frontiers in Oncology. This study proposed a machine-learning-based prediction model, which integrates clinical characteristics (age and smoking history) and radiological profiles of nodules with the artificial intelligence (AI) analysis of LDCT data and Sanmed's liquid biopsy assay results. In a sample of 728 subjects, the model achieved optimal diagnostic performance, outperforming any approaches conducted alone.

Ramping up with applications

Sanmed has established a sound intellectual property protection system and its technological advantage has stretched to far-reaching applications and collaborations. At present, the products are in clinical use in more than 20 leading hospitals in China.

Furthermore, the company's comprehensive solution in early detection of lung cancer attracted a specialist in respiratory diseases. Chunxue Bai, chair of the Chinese Alliance against Lung Cancer and vice president of the Chinese Respiratory Association, plans to partner with the company to conduct a multi-center clinical study of AI-assisted Sanmed's liquid biopsy assay diagnosis of benign and malignant lung nodules in China, enrolling more than 10 hospitals and 100,000 participants.

"We strive to offer cutting-edge products to maximize benefits for both patients and physicians," says Ye. "We believe our non-invasive option will be a useful complementary tool for clinicians in assessing early lung cancer. It could help to improve early lung cancer diagnosis and treatment in patients with malignant nodules while sparing those with benign entities from unnecessary and potentially harmful surgery."

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After 40 Years Of Smoking, She Survived Lung Cancer Thanks To New Treatments

Yuki Noguchi Apr. 12, 2024

Denise Lee grew up in Detroit in the mid-1970s and went to an all-girls Catholic high school. She smoked her first cigarette at age 14 at school, where cigarettes were a popular way of trying to lose weight.

Instead, her nicotine addiction lasted four decades until she quit in her mid-50s.

"At some point it got up as high as 2.5 packs a day," Lee, 62, recalls.

Yet she didn't think about lung cancer risk — until she saw a billboard urging former smokers to get screened. Lee, a retired lawyer living in Fremont, Calif., used to drive past it on her way to work.

"The thing that caught my attention was the fact that it was an African American female on the front," she recalls.

She eventually got the low-dose CT scan recommended for current and former smokers. When doctors found an early, but dangerous, tumor, Lee cried and panicked. Her mother had cared for her father, who'd died of prostate cancer. "My biggest concern was telling my mom," she says.

But that was six years ago, and Lee is cancer free today. Surgery removed the 2-inch tumor in her lung, then new treatments also boosted her immune system, fighting off any recurrence.

Lung cancer remains the most lethal form of the disease, killing about 135,000 Americans a year – more than breast, prostate and colon cancer combined – which is why many people still think of a diagnosis as synonymous with a death sentence. But with new treatments and technology, the survival rates from lung cancer are dramatically improving, allowing some patients with relatively late-stage cancers to live for years longer.

"If you're gonna have lung cancer, now is a good time," Lee says of the advances that saved her.

The key breakthrough, says Robert Winn, a lung cancer specialist at Virginia Commonwealth University, is the ability to better pinpoint the mutations of a patient's particular form of cancer. In the past, treatments were blunt tools that caused lots of collateral damage to healthy parts of the body while treating cancer.

"We've gone from that to molecular characterization of your lung cancer, and it has been a game changer," Winn says. "This is where science and innovation has an impact."

One of those game-changing treatments is called targeted therapy. Scientists identify genetic biomarkers in the mutated cancer cells to target and then deliver drugs that attack those targets, shrinking tumors.

Another is immunotherapy, usually taken as a pill, which stimulates the body's own defense system to identify foreign cells, then uses the immune system's own power to fight the cancer as if it were a virus.

As scientists identify new cancer genes, they're creating an ever-broader array of these drugs.

Combined, these treatments have helped increase national survival rates by 22% in the past five years – a rapid improvement over a relatively short time, despite the fact that screening rates are very slow to increase. Winn says as these treatments get cheaper and readily available, the benefits are even reaching rural and Black populations with historic challenges accessing health care.

The most remarkable thing about the drugs is their ability to, in some cases, reverse late-stage cancers. Chi-Fu Jeffrey Yang, a thoracic surgeon at Massachusetts General Hospital and faculty at Harvard Medical School, recalls seeing scans where large dark shadows of tumor would disappear: "It was remarkable to see the lung cancer completely melting away."

To Yang, such progress feels personal. He lost his beloved grandfather to the disease when Yang was in college. If he were diagnosed today, he might still be alive.

"Helping to take care of him was a big reason why I wanted to be a doctor," Yang says.

But the work of combating lung cancer is far from over; further progress in lung cancer survival hinges largely on getting more people screened.

Low-dose CT scans are recommended annually for those over 50 who smoked the equivalent of a pack a day for 20 years. But nationally, only 4.5% of those eligible get those scans, compared to rates of more than 75% for mammograms.

Andrea McKee, a radiation oncologist and spokesperson for the American Lung Association, says part of the problem is that lung cancer is associated with the stigma of smoking. Patients often blame themselves for the disease, saying: "'I know I did this to myself. And so I don't I don't think I deserve to get screened.'"

McKee says that's a challenge unique to lung cancer. "And it just boggles my mind when I hear that, because, of course, nobody deserves to die of lung cancer."

Denise Lee acknowledges that fear. "I was afraid of what they would find," she admits. But she urges friends and family to get yearly scans, anyway.

"I'm just so grateful that my diagnosis was early because then I had options," she says. "I could have surgery, I could have chemotherapy, I could be a part of a clinical trial."

And all of that saved her life.

Studies Find Nonsmoking Women Getting Lung Cancer But Going Unscreened

Over 50% of women with lung cancer are non-smokers - and that rate is only increasing.

getty

"This year, nearly 250,000 Americans will be diagnosed with lung cancer," President Biden wrote to mark the beginning of National Lung Cancer Awareness Month, which takes place every November. Lung cancer is one of the most common cancers in and the leading cause of cancer death for both men and women - but the president's proclamation didn't include the fact that lung cancer is now affecting women, even non-smoking women, at a higher rate than men.

Historically, lung cancer was known as a men's disease, due to their higher occupational exposure and higher smoking rates than women's. Occupational hazards, such as exposure to asbestos, arsenic, benzene, cadmium, coal tar, disease fuel emissions, formaldehyde, and medical radiation, can all increase the risk of lung cancer. 5.3% of total cancer cases in men are linked to occupational exposure, compared to 2.3% of female cancer cases, since fields with high exposure, such as construction, freight handling, painting, pipefitting, and plumbing, are usually male dominated.

Lung cancer was known as a men's disease; occupational hazards - a common causes of lung cancer - ... [+] were and are present in professions that are male-dominated.

Eva Epker

Similarly, men historically and currently smoke more than women. Cigarette smoking remains the most common cause of lung cancer across sexes, causing 90% of cases in men and 70-80% cases in women. As of 2021, about 13.1% of men smoke while 10.1% of women smoke.

However, over 50% of women with lung cancer worldwide are non-smokers (compared to only 15-20% of men). Non-smoking women also have a higher incidence of lung cancer (19%) than non-smoking men do (9%). And, even when adjusted for smoking status, the female sex is associated with a higher risk of lung cancer. Lung cancer diagnoses have risen 84% among women – but have dropped 36% for men – over the past 40-plus years, and women between the ages of 30 and 49 not only are being diagnosed with lung cancer (when the average age at diagnosis is about 70 years old) but also are being diagnosed at a higher rate than men of the same age.

Although smoking is the most common cause of lung cancer, the percentage of the population that ... [+] smoke or have smoked has been steadily decreasing.

Eva Epker

And yet there isn't any conclusive data explaining these sex-based trends. Possible and partial explanations include the makeup of cigarettes as well as women's hormones, environmental exposure (to air pollution, cooking oil fumes, secondhand smoke, wood combustion, or other carcinogens) and genetics. For genetic specifically, a protein called CYP1A1, which activates carcinogens, is overexpressed in women. Women also have more frequent p53 mutations, which are responsible for 60% of lung cancers, than men do, and have an increased gastrin-releasing peptide receptor - GRPR - that stimulates cancer cell proliferation. These genetic differences may cause women to have a higher susceptibility to carcinogens – substances that increase an individual's risk of cancer – and, subsequently, have higher rates of lung cancer than men have.

But this potentially higher susceptibility isn't reflected in the current lung cancer screening guidelines or the studies that led to the development of those guidelines. The National Lung Screening Study, which started in 2002, recruited 55,000 participants but only 39% were women. Similarly, the NELSON study, which started in 2003, had over 15,000 participants but only 16% were women. Women were, thus, underrepresented in the former and current smokers recruited for these trials – and non-smoking women weren't represented at all. As a result, lung cancer screening eligibility applies to individuals who smoke at least 20 packs a year and are at least 50 years old; there are no sex-based differences in these guidelines, despite the rising cases of lung cancer in both smoking and non-smoking women. As a 2022 review concludes, "The lack of guidelines and risk assessments for light or never smokers predisposes women with lung cancer in particular to be missed with current screening recommendations."

Lung cancer is disproportionately affecting women - but the reasons behind this sex-based ... [+] difference, including the rising rates of cancer in non-smoking women, are largely unknown

Eva Epker

In addition to being ineligible for screening, women, both smokers and non-smokers, may not even notice that they have lung cancer until it has progressed to a late stage. Women are more likely than men to develop lung adenocarcinoma (cancer that develops in the cells that line the outside of the lungs) while men are more likely than women to develop squamous cell carcinoma (cancer that develops in the cells that line the inside of the lungs' airways). Both cancers' symptoms can include a bloody cough, a recurrent or worsening cough, difficulty breathing or swallowing, hoarseness, and swelling in the face and neck veins. However, lung adenocarcinoma can also manifest in abdominal pain, bone pain, headaches, and/or mucus secretion: symptoms that aren't necessarily specific to lung cancer and that may cause the cancer to be misdiagnosed.

In short, non-smoking women are doubly disadvantaged: they usually aren't eligible for lung cancer screenings under the current guidelines because they don't smoke, and their cancer may be missed or dismissed until a stage where it is near-fatal.

Lung cancer is the leading cause of death - and the survival rate only decreases with each ... [+] subsequent stage at diagnosis.

Eva Epker

When their lung cancer is correctly diagnosed and treated, however, both smoking and non-smoking women have shown to respond better to lung cancer treatments than their male peers. Women see more positive results than men across various treatment options – including EGFR inhibitors, platinum-based chemotherapies, surgery, and radiotherapy. Women with lung cancer also survive significantly longer than men, in part due to their treatment and lifestyle choices and the characteristics of their tumor.

But, much like the rising rates of lung cancer in women, the main reason behind their improved survival rates is still unknown, serving only to highlight the sparse research in sex-related differences in lung cancer. Two articles, both published in 2021 echo this fact. One states, "The double-edged sword of female sex and lung cancer necessitates that future studies aim to better understand factors (environmental, genetic, hormonal) in addition to smoking intensity and duration that may affect risk". The other argues for "targeted therapies" and "screening recommendations" that reflect the role of sex, noting that "the data regarding optimal care and outcomes is still lagging behind" for women.

These calls for sex-specific research, the rising rates of lung cancer in women, especially non-smoking women, and federal programs – including the reignited Cancer Moonshot program and recent White House Initiative on Women's Health Research – all may help catalyze change and improve the lives of both smoking and nonsmoking women. As President Biden wrote in his proclamation on National Lung Cancer Awareness Month, "During National Lung Cancer Awareness Month, the First Lady and I have one message to the Nation: There is hope."

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