Challenges and Opportunities in Cancer Immunotherapy: A Society for Immunotherapy of Cancer (SITC) Strategic Vision

Cancer immunotherapy has flourished over the last 10-15 years, transforming the practice of oncology and providing long-term clinical benefit to some patients. During this time, three distinct classes of immune checkpoint inhibitors, chimeric antigen receptor-T cell therapies specific for two targets, and two distinct classes of bispecific T cell engagers, a vaccine, and an oncolytic virus have joined cytokines as a standard of cancer care. At the same time, scientific progress has delivered vast amounts of new knowledge. For example, advances in technologies such as single-cell sequencing and spatial transcriptomics have provided deep insights into the immunobiology of the tumor microenvironment. With this rapid clinical and scientific progress, the field of cancer immunotherapy is currently at a critical inflection point, with potential for exponential growth over the next decade. Recognizing this, the Society for Immunotherapy of Cancer convened a diverse group of experts in cancer immunotherapy representing academia, the pharmaceutical and biotechnology industries, patient advocacy, and the regulatory community to identify current opportunities and challenges with the goal of prioritizing areas with the highest potential for clinical impact. The consensus group identified seven high-priority areas of current opportunity for the field: mechanisms of antitumor activity and toxicity; mechanisms of drug resistance; biomarkers and biospecimens; unique aspects of novel therapeutics; host and environmental interactions; premalignant immunity, immune interception, and immunoprevention; and clinical trial design, endpoints, and conduct. Additionally, potential roadblocks to progress were discussed, and several topics were identified as cross-cutting tools for optimization, each with potential to impact multiple scientific priority areas. These cross-cutting tools include preclinical models, data curation and sharing, biopsies and biospecimens, diversification of funding sources, definitions and standards, and patient engagement. Finally, three key guiding principles were identified that will both optimize and maximize progress in the field. These include engaging the patient community; cultivating diversity, equity, inclusion, and accessibility; and leveraging the power of artificial intelligence to accelerate progress. Here, we present the outcomes of these discussions as a strategic vision to galvanize the field for the next decade of exponential progress in cancer immunotherapy

Trends in complementary/alternative medicine use by breast cancer survivors: Comparing survey data from 1998 and 2005

BACKGROUND: Use of complementary and alternative medicine (CAM) by women with breast cancer is often said to be increasing, yet few data exist to confirm this commonly held belief. The purpose of this paper is to compare overall patterns of CAM use, as well as use of specific products and therapies at two different points in time (1998 vs 2005) by women diagnosed with breast cancer. METHODS: Surveys were mailed to women randomly selected from the Ontario Cancer Registry (Canada) in the spring of 1998 (n = 557) and again in the spring of 2005(n = 877). RESULTS: The response rates were 76.3% in 1998 and 63% in 2005. In 1998, 66.7% of women reported using either a CAM product/therapy or seeing a CAM therapist at some time in their lives as compared with 81.9% in 2005 (p = 0.0002). Increases were seen in both use of CAM products/therapies (62% in 1998 vs. 70.6% in 2005) and visits to CAM practitioners (39.4% of respondents in 1998 vs 57.4% of respondents in 2005). Women in 2005 reported that 41% used CAM for treating their breast cancer. The most commonly used products and practitioners for treating breast cancer as reported in 2005 were green tea, vitamin E, flaxseed, vitamin C, massage therapists and dietitians/nutritionists. CONCLUSION: CAM use (both self-medication with products and visits to CAM practitioners) increased significantly from 1998 to 2005. Now that more than 80% of all women with breast cancer report using CAM (41% in a specific attempt to management their breast cancer), CAM use can no longer be regarded as an "alternative" or unusual approach to managing breast cancer

The impact of patient characteristics and lifestyle factors on the risk of an ipsilateral event after a primary DCIS: a systematic review

ObjectiveThe ma­jor­ity of ‘low-risk’ (grade I/​II) Duc­tal Car­ci­noma In Situ (DCIS) may not progress to in­va­sive breast can­cer dur­ing a wom­en's life­time. There­fore, the safety of ac­tive sur­veil­lance ver­sus stan­dard sur­gi­cal treat­ment for DCIS is prospec­tively be­ing eval­u­ated in clin­i­cal tri­als. If proven safe and se­lec­tively im­ple­mented in clin­i­cal prac­tice, a sig­nif­i­cant group of women with low-risk DCIS may forego surgery and ra­dio­ther­apy in the fu­ture. Iden­ti­fi­ca­tion of mod­i­fi­able and non-mod­i­fi­able risk fac­tors as­so­ci­ated with prog­no­sis af­ter a pri­mary DCIS would also en­hance our care of women with low-risk DCIS.MethodsTo iden­tify mod­i­fi­able and non-mod­i­fi­able risk fac­tors for sub­se­quent breast events af­ter DCIS, we per­formed a sys­tem­atic lit­er­a­ture search in PUBMED, EM­BASE and Sco­pus.ResultsSix out of the 3870 ar­ti­cles re­trieved were in­cluded for fi­nal data ex­trac­tion. These six stud­ies in­cluded a to­tal of 4950 pa­tients with pri­mary DCIS and 640 recorded sub­se­quent breast events. There was mod­er­ate ev­i­dence for an as­so­ci­a­tion of a fam­ily his­tory of breast can­cer, pre­menopausal sta­tus, high BMI, and high breast den­sity with a sub­se­quent breast can­cer or fur­ther DCIS.ConclusionThere is a lim­ited num­ber of re­cent stud­ies pub­lished on the im­pact of mod­i­fi­able and non-mod­i­fi­able risk fac­tors on sub­se­quent events af­ter DCIS. The avail­able ev­i­dence is in­suf­fi­cient to iden­tify po­ten­tial tar­gets for risk re­duc­tion strate­gies, re­flect­ing the rel­a­tively small num­bers and the lack of long-term fol­low-up in DCIS, a low-event con­di­tion.</p

Association of DCIS Size and Margin Status With Risk of Developing Breast Cancer Post-Treatment: Multinational, Pooled Cohort Study

OBJECTIVE: To examine the association between size and margin status of ductal carcinoma in situ (DCIS) and risk of developing ipsilateral invasive breast cancer and ipsilateral DCIS after treatment, and stage and subtype of ipsilateral invasive breast cancer. DESIGN: Multinational, pooled cohort study. SETTING: Four large international cohorts. PARTICIPANTS: Patient level data on 47 695 women with a diagnosis of pure, primary DCIS between 1999 and 2017 in the Netherlands, UK, and US who underwent surgery, either breast conserving or mastectomy, often followed by radiotherapy or endocrine treatment, or both. MAIN OUTCOME MEASURES: The main outcomes were 10 year cumulative incidence of ipsilateral invasive breast cancer and ipsilateral DCIS estimated in relation to DCIS size and margin status, and adjusted hazard ratios and 95% confidence intervals, estimated using multivariable Cox proportional hazards analyses with multiple imputed data RESULTS: The 10 year cumulative incidence of ipsilateral invasive breast cancer was 3.2%. In women who underwent breast conserving surgery with or without radiotherapy, only adjusted risks for ipsilateral DCIS were significantly increased for larger DCIS (20-49 mm) compared with DCIS(hazard ratio 1.38, 95% confidence interval 1.11 to 1.72). Risks for both ipsilateral invasive breast cancer and ipsilateral DCIS were significantly higher with involved compared with clear margins (invasive breast cancer 1.40, 1.07 to 1.83; DCIS 1.39, 1.04 to 1.87). Use of adjuvant endocrine treatment was not significantly associated with a lower risk of ipsilateral invasive breast cancer compared to treatment with breast conserving surgery only (0.86, 0.62 to 1.21). In women who received breast conserving treatment with or without radiotherapy, higher DCIS grade was not significantly associated with ipsilateral invasive breast cancer, only with a higher risk of ipsilateral DCIS (grade 1: 1.42, 1.08 to 1.87; grade 3: 2.17, 1.66 to 2.83). Higher age at diagnosis was associated with lower risk (per year) of ipsilateral DCIS (0.98, 0.97 to 0.99) but not ipsilateral invasive breast cancer (1.00, 0.99 to 1.00). Women with large DCIS (≥50 mm) more often developed stage III and IV ipsilateral invasive breast cancer compared to women with DCISfound. CONCLUSIONS: The association of DCIS size and margin status with ipsilateral invasive breast cancer and ipsilateral DCIS was small. When these two factors were added to other known risk factors in multivariable models, clinicopathological risk factors alone were found to be limited in discriminating between low and high risk DCIS

CALGB 40603 (Alliance): Long-Term Outcomes and Genomic Correlates of Response and Survival After Neoadjuvant Chemotherapy With or Without Carboplatin and Bevacizumab in Triple-Negative Breast Cancer

PURPOSECALGB 40603 (NCT00861705), a 2 × 2 randomized phase II trial, demonstrated that adding carboplatin or bevacizumab to weekly paclitaxel (wP) followed by doxorubicin and cyclophosphamide significantly increased the pathologic complete response (pCR) rate in stage II-III triple-negative breast cancer. We now report long-term outcomes (LTOs) and correlative science end points.PATIENTS AND METHODSThe Kaplan-Meier method was used to estimate LTOs in 443 patients who initiated study treatment. Log-rank tests and Cox proportional hazards models evaluated the impact of clinical characteristics, pathologic response, calculated residual cancer burden (RCB) in patients with residual disease (RD), treatment assignment, and dose delivery during wP on LTOs, including event-free survival (EFS). Genomic predictors of treatment response and outcomes were assessed on pretreatment tumor samples by mRNA sequencing.RESULTSAmong baseline characteristics, only the clinical stage was associated with LTOs. At a median follow-up of 7.9 years, LTOs were not significantly improved with either carboplatin or bevacizumab, overall or in patients with basal-like subtype cancers by genomic analysis. Patients with pCR (n = 205, 46.3%) had significantly higher 5-year EFS (85.5% v 56.6%, log-rank P <.0001) and overall survival (87.9% v 63.4%, P <.0001) rates compared with patients with RD, even those with RCB class I. Among clinical and genomic features, evidence of immune activation, including tumor-infiltrating lymphocytes and low B-cell receptor evenness, was associated with pCR and improved EFS.CONCLUSIONDespite higher pCR rates, neither carboplatin nor bevacizumab appeared to improve LTOs although the study was not powered to assess these secondary end points. pCR was associated with superior LTOs even when compared with minimal RD. Markers of immune activation in pretreatment tumor biopsies were independently associated with higher pCR rates and improved survival

Microcalcification crystallography as a potential marker of DCIS recurrence

Ductal carcinoma in-situ (DCIS) accounts for 20-25% of all new breast cancer diagnoses. DCIS has an uncertain risk of progression to invasive breast cancer and a lack of predictive biomarkers may result in relatively high levels (~ 75%) of overtreatment. To identify unique prognostic biomarkers of invasive progression, crystallographic and chemical features of DCIS microcalcifications have been explored. Samples from patients with at least 5-years of follow up and no known recurrence (174 calcifications in 67 patients) or ipsilateral invasive breast cancer recurrence (179 microcalcifications in 57 patients) were studied. Significant differences were noted between the two groups including whitlockite relative mass, hydroxyapatite and whitlockite crystal maturity and, elementally, sodium to calcium ion ratio. A preliminary predictive model for DCIS to invasive cancer progression was developed from these parameters with an AUC of 0.797. These results provide insights into the differing DCIS tissue microenvironments, and how these impact microcalcification formation. [Abstract copyright: © 2023. The Author(s).

Mechanisms that clear mutations drive field cancerization in mammary tissue

Oncogenic mutations are abundant in the tissues of healthy individuals, but rarely form tumours1–3. Yet, the underlying protection mechanisms are largely unknown. To resolve these mechanisms in mouse mammary tissue, we use lineage tracing to map the fate of wild-type and Brca1−/−;Trp53−/− cells, and find that both follow a similar pattern of loss and spread within ducts. Clonal analysis reveals that ducts consist of small repetitive units of self-renewing cells that give rise to short-lived descendants. This offers a first layer of protection as any descendants, including oncogenic mutant cells, are constantly lost, thereby limiting the spread of mutations to a single stem cell-descendant unit. Local tissue remodelling during consecutive oestrous cycles leads to the cooperative and stochastic loss and replacement of self-renewing cells. This process provides a second layer of protection, leading to the elimination of most mutant clones while enabling the minority that by chance survive to expand beyond the stem cell-descendant unit. This leads to fields of mutant cells spanning large parts of the epithelial network, predisposing it for transformation. Eventually, clone expansion becomes restrained by the geometry of the ducts, providing a third layer of protection. Together, these mechanisms act to eliminate most cells that acquire somatic mutations at the expense of driving the accelerated expansion of a minority of cells, which can colonize large areas, leading to field cancerization