Highlights in Cancer Research: March 2024

The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).

The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.

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10. Early-Stage Breast Cancer Detection in Breast Milk

1. IL-1β+ macrophages fuel pathogenic inflammation in pancreatic cancer
2. Deterministic reprogramming of neutrophils within tumors
3. A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer
4. Manipulating mitochondrial electron flow enhances tumor immunogenicity
5. Rapid adaptation to CDK2 inhibition exposes intrinsic cell-cycle plasticity
6. Acquisition of suppressive function by conventional T cells limits antitumor immunity upon Treg depletion
7. Cooperative CAR targeting to selectively eliminate AML and minimize escape
8. DNA hypomethylation silences anti-tumor immune genes in early prostate cancer and CTCs
9. Immune evasion of dormant disseminated tumor cells is due to their scarcity and can be overcome by T cell immunotherapies.
10. Early-Stage Breast Cancer Detection in Breast Milk

Saura, C. et al. Cancer Discov 13 (10), 2180–2191 (2023).
doi: doi.org/10.1158/2159-8290.CD-22-1340.

Summary of the findings

Breast Cancer (BC) diagnosed during pregnancy (PrBC) or postpartum (PPBC) is independently associated with almost 30% lower 5-year survival rates than non-pregnancy-linked BC, primarily due to delays in diagnosis and presentation at an advanced stage. The limited sensitivity of standard imaging tools, coupled with morphological breast changes, contributes to the challenge of early tumor detection during pregnancy and after birth. Adjusting for clinicopathological factors does not mitigate the doubled metastatic risk of PPBC. Recognizing the urgent need for new approaches to early postpartum diagnosis, we hypothesized that breast milk (BM) could serve as an excellent source of tumor genetic material, a proposition not previously demonstrated.

Therefore, we investigated the presence of circulating tumor DNA (ctDNA) in BM and plasma from women with PrBC or PPBC and a healthy cohort. Our findings indicate that ctDNA is present in 87% of BM samples using droplet digital PCR and is detectable by targeted Next-Generation Sequencing (NGS) in 71.4% of cases, recapitulating the mutational profile of the tumors. In contrast, a mere 8% of plasma samples tested positive. Notably, in two cases, BM showed positive ctDNA levels at 18 and 6 months prior to diagnosis, suggesting a potential future use of BM as a method for early PPBC detection.

A. Study design. Women diagnosed of breast cancer (BC) during pregnancy or postpartum, with available treatment naïve tumor biopsy and breast milk (BM) samples, were enrolled (n=15). Whenever possible, BM from both breasts and blood-derived plasma were collected in parallel. A group of healthy volunteers donated BM from both breasts as controls (n=12). B. Analysis. DNA extracted from all samples was analyzed for variant detection through NGS, demonstrating a 73,3% of positivity in the ipsilateral BM from BC diagnosed women, 7,7% of the plasma samples and none of the contralateral BM. As control, BM samples from the healthy group were all negative. Mutant allelic fractions (MAF %) are depicted in a green colour scale. Dashed-lined squares represent absent samples.

Future impact

Our data demonstrates a high prevalence of ctDNA shedding in BM, paving the way for its use as a clinically useful tool for cancer screening in a targeted population. This could include germline carriers associated with BC, women with a history of BC, or those with previous chest radiation. Further research in a larger cohort is necessary to establish a required high specificity for an acceptable positive predictive value, a crucial factor for any early detection method. In a society where factors increasing the risk of BC in young women are on the rise, such as delayed age at first pregnancy or a decrease in the number of newborns per woman, there is a need to investigate novel strategies for early PPBC detection.