Real world study of sacituzumab govitecan in metastatic triple-negative breast cancer in the United Kingdom.

BACKGROUND: Treatment options for pre-treated patients with metastatic triple-negative breast cancer (mTNBC) remain limited. This is the first study to assess the real-world safety and efficacy of sacituzumab govitecan (SG) in the UK. METHODS: Data was retrospectively collected from 16 tertiary UK cancer centres. Pts had a diagnosis of mTNBC, received at least two prior lines of treatment (with at least one being in the metastatic setting) and received at least one dose of SG. RESULTS: 132 pts were included. Median age was 56 years (28-91). All patients were ECOG performance status (PS) 0-3 (PS0; 39, PS1; 76, PS2; 16, PS3;1). 75% (99/132) of pts had visceral metastases including 18% (24/132) of pts with CNS disease. Median PFS (mPFS) was 5.2 months (95% CI 4.5-6.6) with a median OS (mOS) of 8.7 months (95% CI 6.8-NA). The most common adverse events (AEs) were fatigue (all grade; 82%, G3/4; 14%), neutropenia (all grade; 55%, G3/4; 29%), diarrhoea (all grade; 58%, G3/4, 15%), and nausea (all grade; 38%, G3/4; 3%). SG dose reduction was required in 54% of pts. CONCLUSION: This study supports significant anti-tumour activity in heavily pre-treated pts with mTNBC. Toxicity data aligns with clinical trial experience.

Gut-disc axis: A cause of intervertebral disc degeneration and low back pain?

PURPOSE: Low back pain (LBP), a widely prevalent and costly disease around the world, is mainly caused by intervertebral disc (IVD) degeneration (IDD). Although numerous factors may trigger this degenerative process, microbiome dysbiosis has recently been implicated as one of the likely causes. However, the exact relationship between the microbiome and IDD is not well understood. This review summarizes the potential mechanisms and discusses microbiome dysbiosis's possible influence on IDD and LBP. METHODS: Prospective literature review. RESULTS: Alterations in microbiome composition and host responses to the microbiota causing pathological bone development and involution, led to the concept of gut-bone marrow axis and gut-bone axis. Moreover, the concept of the gut-disc axis was also proposed to explain the microbiome's role in IDD and LBP. According to the existing evidence, the microbiome could be an important factor for inducing and aggravating IDD through changing or regulating the outside and inside microenvironment of the IVD. Three potential mechanisms by which the gut microbiota can induce IVD and cause LBP are: (1) translocation of the bacteria across the gut epithelial barrier and into the IVD, (2) regulation of the mucosal and systemic immune system, and (3) regulation of nutrient absorption and metabolites formation at the gut epithelium and its diffusion into the IVD. Furthermore, to investigate whether IVD is initiated by pathogenic bacteria and establish the correlation between the presence of certain microbial groups with the disease in question, microbiome diversity analysis based on16S rRNA data can be used to characterise stool/blood microbiota from IVD patients. CONCLUSION: Future studies on microbiome, fungi and viruses in IDD is necessary to revolutionize our thinking about their possible role in the development of IVD diseases. Furthermore, we believe that inflammation inhibition and interruption of amplification of cascade reaction in IVD by targeting the gut and IVD microbiome is worthwhile for the treatment of IDD and LBP. LEVEL OF EVIDENCE I: Diagnostic: individual cross-sectional studies with the consistently applied reference standard and blinding.

Pathological complete response to neoadjuvant systemic therapy in 789 early and locally advanced breast cancer patients: The Royal Marsden experience.

PURPOSE: Pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) for breast cancer predicts the risk of recurrence and increasingly may indicate the need for additional therapy postoperatively. METHODS: We identified non-metastatic breast cancer patients receiving NACT during 2013-2017. Patients' and disease characteristics, rates of pCR (ypT0-is ypN0), toxicities, dose delays and reductions, and survival outcomes were recorded. RESULTS: 789 patients had median age of 50 years. 67.8% had stage II disease, 71.1% had grade 3 , and 91.8% had ductal histopathology. 32.8% had estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, 25.5% had triple-negative (TN), and 38.0% HER2-positive disease. 6.8% received platinum. 48.2% of the HER2-positive patients received trastuzumab and pertuzumab and 51.8% received trastuzumab. Overall pCR rate was 33.5% and differed according to disease subtype, receptor status, grade, histology, and early discontinuation, but not according to age, dose reductions/delays, or year of treatment. The addition of pertuzumab to trastuzumab marginally improved the pCR rates. Survival outcomes were better following pCR. CONCLUSIONS: In our analysis, pCR rates are consistent with the published data. Even with contemporary therapies, many patients have residual disease following NACT, suggesting a significant risk of recurrence, and may benefit from additional postoperative systemic therapy.

Potentials of "stem cell-therapy" in pancreatic cancer: An update.

In recent times, cell-therapies like T-activated cells, dendritic cells and natural killer cells have shown increasing promise in treating cancers as evidenced by both animal and human studies in the literature. In addition, stem cells are also being considered as potent anti-cancer agents since they act through multi-pronged approaches (chemokines, cytokines, paracrine action). In this review, we have attempted to discuss the inferences of studies that have used different sub-types of stem cells namely mesenchymal stem cells (MSCs), hematopoietic stem cells (HSCs) and neural stem cells (NSCs) in in-vitro/in-vivo mice and/or human studies as a treatment modality for pancreatic cancer. Pancreatic cancers are diagnosed in late/metastatic stages hence limiting its progress to partial/disease-free status. Recent literature supports evidences of stem cell therapy in pancreatic cancer with promising results; yet their impact remains inconclusive due to limited studies in human subjects. With reference to the treatment options for pancreatic cancer, the most studied sub-type of stem cells was HSCs as evident from the available clinical trials. The suggested mechanism of the HSC-transplantation is presumably via the graft-versus-tumor effect that elicits an anti-tumor immune response activated by the T-cell repertoires. On the other hand, the property of MSCs like tropism, migration to tumor site and activation of host immune cells by its secretome, appear to be able to regulate pancreatic tumor microenvironment. Further, drug delivery potential could be mediated via engineered MSCs to enhance the bioavailability of drug/prodrug at tumor site. Conclusively, stem cells have shown great potentials as next-generation therapeutic options.

The association between low virulence organisms in different locations and intervertebral disc structural failure: A meta-analysis and systematic review.

Many factors may trigger intervertebral disc (IVD) structural failure (intervertebral disc degeneration (IDD) and endplate changes), including inflammation, infection, dysbiosis, and the downstream effects of chemical factors. Of these, microbial diversity in the IVD and elsewhere in the body has been considered as one of the potential reasons for disc structural failure. The exact relationships between microbial colonization and IVD structural failure are not well understood. This meta-analysis aimed to investigate the impact of microbial colonization and its location (such as skin, IVD, muscle, soft tissues, and blood) on IVD structural failure and corresponding low back pain (LBP) if any. We searched four online databases for potential studies. The potential relationships between microbial colonization in different sample sources (such as skin, IVD, muscle, soft tissues, and blood) and IDD and endplate change were considered as primary outcomes. Odds ratio (OR) and 95% confidence intervals (CI) for direct comparisons were reported. Grading of Recommendations Assessment, Development and Evaluation (GRADE) scale was used to assess the quality of evidence. Twenty-five cohort studies met the selection criteria. Overall pooled prevalence of microbial colonization in 2419 patients with LBP was 33.2% (23.6%-43.6%). The pooled prevalence of microbial colonization in 2901 samples was 29.6% (21.0%-38.9%). Compared with the patients without endplate change, the patients with endplate changes had higher rates of microbial colonization of disc (OR = 2.83; 95% CI = 1.93-4.14; I 2 = 37.6%; p = 0.108). The primary pathogen was Cutibacterium acnes which was present in 22.2% of cases (95% CI = 13.3%-32.5%; I 2 = 96.6%; p = 0.000). This meta-analysis and systematic review found low-quality grade evidence for an association between microbial colonization of disc with endplate changes. The primary pathogen was C. acnes. Due to lack of enough high-quality studies and methodological limitations of this review, further studies are required to improve our understanding of the potential relationships and mechanisms of microbiota, dysbiosis, IVD colonization and IVD structural failure.

Phase 1 evaluation of an elastomeric nucleus pulposus device as an option to augment disc at microdiscectomy: Experimental results from biomechanical and biocompatibility testing and first in human.

Objective: Whilst microdiscectomy is an excellent reliever of pain for recalcitrant lumbar disc herniation (LDH), it has a high failure rate over time due to the ensuing reduction in mechanical stabilization and support of the spine. One option is to clear the disc and replace it with a nonhygroscopic elastomer. Here, we present the evaluation of biomechanical and biological behavior of a novel elastomeric nucleus device (Kunovus disc device [KDD]), consisting of a silicone jacket and a two-part in situ curing silicone polymer filler. Materials and Methods: ISO 10993 and American Society for Testing and Materials (ASTM) standards were used to evaluate the biocompatibility and mechanics of KDD. Sensitization, intracutaneous reactivity, acute systemic toxicity, genotoxicity, muscle implantation study, direct contact matrix toxicity assay, and cell growth inhibition assay were performed. Fatigue test, static compression creep testing, expulsion testing, swell testing, shock testing, and aged fatigue testing were conducted to characterize the mechanical and wear behavior of the device. Cadaveric studies to develop a surgical manual and evaluate feasibility were conducted. Finally, a first-in-human implantation was conducted to complete the proof of principle. Results: The KDD demonstrated exceptional biocompatibility and biodurability. Mechanical tests showed no Barium-containing particles in fatigue test, no fracture of nucleus in static compression creep testing, no extrusion and swelling, and no material failure in shock and aged fatigue testing. Cadaver training sessions showed that KDD was deemed implantable during microdiscectomy procedures in a minimally invasive manner. Following IRB approval, the first implantation in a human showed no intraoperative vascular and neurological complications and demonstrated feasibility. This successfully completed Phase 1 development of the device. Conclusion: The elastomeric nucleus device may mimic native disc behavior in mechanical tests, offering an effective way for treating LDH by way of Phase 2 and subsequent clinical trials or postmarket surveillance in the future.

The role of PARP inhibitors in gastrointestinal cancers.

The use of BReast CAncer (BRCA) mutations as biomarkers for sensitivity to DNA damage response (DDR) targeted drugs and platinum agents is well documented in breast and gynaecological cancers. More recently the successful use DDR targeted therapies including poly (ADP-ribose) polymerases (PARP) inhibitors has been shown to extend to other germline and somatic deficiencies within the homologous recombination (HR) pathway (Farmer et al., 2005; Turner et al., 2019; Li and Heyer, 2008). Gastrointestinal (GI) cancers are lagging behind other tumour types when it comes to personalising treatment with targeted therapies. Current methods of identifying PARP-inhibitor sensitivity in gastrointestinal cancers are based on analogies from other cancer types despite there being a lack of uniformity in determining HR status between tumour types. There is an urgent clinical need to better understand the treatment implications of DDR alterations in gastrointestinal cancers. We have reviewed PARP-inhibitor use in pancreatic, gastroesophageal, hepatobiliary and colorectal cancers and explored HRD as a biomarker for sensitivity to PARP-inhibitors.

Barriers to optimal breast milk provision in the neonatal intensive care unit.

OBJECTIVE: This study examines comprehensive patient and process factors that influence breast milk use in the NICU setting. STUDY DESIGN: We examined the association of maternal, neonatal, and family factors and lactation support systems to identify gaps in breast milk use in a retrospective study of 865 infants born in 23-41 weeks gestation admitted to the NICU. RESULTS: Breast milk at discharge for all infants was 89.3%, for extremely preterm 82.3%, moderately preterm 91.4%, late preterm 86.5%, and term 92.7%. Prematurity (OR 0.31 [0.17-0.56]), low birth weight, morbidities, Black maternal race (OR 0.20 [0.07-0.57]) and public insurance (OR 0.54 [0.34-0.85]) were associated with decreased breast milk use. Early initiation of feeds was associated with increased breast milk use. CONCLUSIONS: There is a need to increase social as well as hospital support systems to address gaps in breast milk use in the NICU.

Pulmonary tuberculosis presenting as acute respiratory distress syndrome.

Pulmonary tuberculosis (TB) may present in the form of parenchymal disease or extraparenchymal disease. Patients with TB as a primary cause of respiratory failure requiring mechanical ventilation have been reported to have mortality rates ranging between 47% and 80%. However, acute respiratory distress syndrome (ARDS) as a presentation of TB is rarely reported. We describe two cases of immunocompetent women presenting with ARDS. They were initially worked up for viral aetiologies in view of the ongoing COVID-19 pandemic but were later diagnosed to have microbiologically proven parenchymal pulmonary TB. One of our patients succumbed to nosocomial pneumonia, while the other was discharged to follow-up.

Clinical predictors of long COVID-19 and phenotypes of mild COVID-19 at a tertiary care centre in India.

A variable proportion of patients develop persistent/prolonged symptoms of Coronavirus Disease 2019 (COVID-19) infection (long COVID). We aimed to study the clinical predictors of persistent symptoms in patients with mild COVID-19 at 30 days post discharge (long COVID-19). We also tried to identify symptom clusters among mild COVID-19 patients. Fifty-seven patients admitted at a tertiary care centre after a positive RT-PCR report over a period of 2 months, were enrolled in the study. Details of presentation, history of illness, laboratory investigations and disease outcomes were recorded from documented medical records and discharge slip. The patients were contacted (telephonically) at 30 days after discharge and enquired regarding persistent symptoms, if any. Follow up data at 30 days post-discharge was available for 53 patients. Among them, the most common persistent symptom was fatigue (22.6%), followed by cough (9.4%) and myalgias (7.5%). There was a significant association of persistent symptoms with diarrhoea at presentation [OR 14.26 (95% CI 2.30-142.47; p = 0.009] and gap between symptom onset and admission [OR 1.40 (95% CI 1.08-1.93; p = 0.020] on multivariate logistic regression analysis. On cluster analysis, three phenotypes of mild COVID-19 were identified, which may have implications on monitoring and management. There appears to be a positive association of diarrhoea as a presenting manifestation and gap between symptom onset and admission with the persistence of symptoms classified as long COVID-19, even in mild illness. We also identified multiple phenotypes of mild COVID-19 illness, which warrant further exploration.

Systemic Anti-Cancer Therapy and Metastatic Cancer Are Independent Mortality Risk Factors during Two UK Waves of the COVID-19 Pandemic at University College London Hospital.

An increased mortality risk was observed in patients with cancer during the first wave of COVID-19. Here, we describe determinants of mortality in patients with solid cancer comparing the first and second waves of COVID-19. A retrospective analysis encompassing two waves of COVID-19 (March-May 2020; December 2020-February 2021) was performed. 207 patients with cancer were matched to 452 patients without cancer. Patient demographics and oncological variables such as cancer subtype, staging and anti-cancer treatment were evaluated for association with COVID-19 mortality. Overall mortality was lower in wave two compared to wave one, HR 0.41 (95% CI: 0.30-0.56). In patients with cancer, mortality was 43.6% in wave one and 15.9% in wave two. In hospitalized patients, after adjusting for age, ethnicity and co-morbidities, a history of cancer was associated with increased mortality in wave one but not wave two. In summary, the second UK wave of COVID-19 is associated with lower mortality in hospitalized patients. A history of solid cancer was not associated with increased mortality despite the dominance of the more transmissible B.1.1.7 SARS-CoV-2 variant. In both waves, metastatic disease and systemic anti-cancer treatment appeared to be independent risk factors for death within the combined cancer cohort.

Specialist palliative and end-of-life care for patients with cancer and SARS-CoV-2 infection: a European perspective.

BACKGROUND: Specialist palliative care team (SPCT) involvement has been shown to improve symptom control and end-of-life care for patients with cancer, but little is known as to how these have been impacted by the COVID-19 pandemic. Here, we report SPCT involvement during the first wave of the pandemic and compare outcomes for patients with cancer who received and did not receive SPCT input from multiple European cancer centres. METHODS: From the OnCovid repository (N = 1318), we analysed cancer patients aged ⩾18 diagnosed with COVID-19 between 26 February and 22 June 2020 who had complete specialist palliative care team data (SPCT+ referred; SPCT- not referred). RESULTS: Of 555 eligible patients, 317 were male (57.1%), with a median age of 70 years (IQR 20). At COVID-19 diagnosis, 44.7% were on anti-cancer therapy and 53.3% had ⩾1 co-morbidity. Two hundred and six patients received SPCT input for symptom control (80.1%), psychological support (54.4%) and/or advance care planning (51%). SPCT+ patients had more 'Do not attempt cardio-pulmonary resuscitation' orders completed prior to (12.6% versus 3.7%) and during admission (50% versus 22.1%, p < 0.001), with more SPCT+ patients deemed suitable for treatment escalation (50% versus 22.1%, p < 0.001). SPCT involvement was associated with higher discharge rates from hospital for end-of-life care (9.7% versus 0%, p < 0.001). End-of-life anticipatory prescribing was higher in SPCT+ patients, with opioids (96.3% versus 47.1%) and benzodiazepines (82.9% versus 41.2%) being used frequently for symptom control. CONCLUSION: SPCT referral facilitated symptom control, emergency care and discharge planning, as well as high rates of referral for psychological support than previously reported. Our study highlighted the critical need of SPCTs for patients with cancer during the pandemic and should inform service planning for this population.

Systemic pro-inflammatory response identifies patients with cancer with adverse outcomes from SARS-CoV-2 infection: the OnCovid Inflammatory Score.

BACKGROUND: Patients with cancer are particularly susceptible to SARS-CoV-2 infection. The systemic inflammatory response is a pathogenic mechanism shared by cancer progression and COVID-19. We investigated systemic inflammation as a driver of severity and mortality from COVID-19, evaluating the prognostic role of commonly used inflammatory indices in SARS-CoV-2-infected patients with cancer accrued to the OnCovid study. METHODS: In a multicenter cohort of SARS-CoV-2-infected patients with cancer in Europe, we evaluated dynamic changes in neutrophil:lymphocyte ratio (NLR); platelet:lymphocyte ratio (PLR); Prognostic Nutritional Index (PNI), renamed the OnCovid Inflammatory Score (OIS); modified Glasgow Prognostic Score (mGPS); and Prognostic Index (PI) in relation to oncological and COVID-19 infection features, testing their prognostic potential in independent training (n=529) and validation (n=542) sets. RESULTS: We evaluated 1071 eligible patients, of which 625 (58.3%) were men, and 420 were patients with malignancy in advanced stage (39.2%), most commonly genitourinary (n=216, 20.2%). 844 (78.8%) had ≥1 comorbidity and 754 (70.4%) had ≥1 COVID-19 complication. NLR, OIS, and mGPS worsened at COVID-19 diagnosis compared with pre-COVID-19 measurement (p<0.01), recovering in survivors to pre-COVID-19 levels. Patients in poorer risk categories for each index except the PLR exhibited higher mortality rates (p<0.001) and shorter median overall survival in the training and validation sets (p<0.01). Multivariable analyses revealed the OIS to be most independently predictive of survival (validation set HR 2.48, 95% CI 1.47 to 4.20, p=0.001; adjusted concordance index score 0.611). CONCLUSIONS: Systemic inflammation is a validated prognostic domain in SARS-CoV-2-infected patients with cancer and can be used as a bedside predictor of adverse outcome. Lymphocytopenia and hypoalbuminemia as computed by the OIS are independently predictive of severe COVID-19, supporting their use for risk stratification. Reversal of the COVID-19-induced proinflammatory state is a putative therapeutic strategy in patients with cancer.

Cancer History and Systemic Anti-Cancer Therapy Independently Predict COVID-19 Mortality: A UK Tertiary Hospital Experience.

BACKGROUND: The COVID-19 pandemic remains a pressing concern to patients with cancer as countries enter the second peak of the pandemic and beyond. It remains unclear whether cancer and its treatment contribute an independent risk for mortality in COVID-19. METHODS: We included patients at a London tertiary hospital with laboratory confirmed SARS-CoV-2 infection. All patients with a history of solid cancer were included. Age- and sex-matched patients without cancer were randomly selected. Patients with hematological malignancies were excluded. RESULTS: We identified 94 patients with cancer, matched to 226 patients without cancer. After adjusting for age, ethnicity, and co-morbidities, patients with cancer had increased mortality following COVID-19 (HR 1.57, 95% CI:1.04-2.4, p = 0.03). Increasing age (HR 1.49 every 10 years, 95% CI:1.25-1.8, p < 0.001), South Asian ethnicity (HR 2.92, 95% CI:1.73-4.9, p < 0.001), and cerebrovascular disease (HR 1.93, 95% CI:1.18-3.2, p = 0.008) also predicted mortality. Within the cancer cohort, systemic anti-cancer therapy (SACT) within 60 days of COVID-19 diagnosis was an independent risk factor for mortality (HR 2.30, 95% CI: 1.16-4.6, p = 0.02). CONCLUSIONS: Along with known risk factors, cancer and SACT confer an independent risk for mortality following COVID-19. Further studies are needed to understand the socio-economic influences and pathophysiology of these associations.

Health-Related Quality of Life and Experiences of Sarcoma Patients during the COVID-19 Pandemic.

Sarcomas are rare cancers with a spectrum of clinical needs and outcomes. We investigated care experiences and health-related quality of life (HRQoL) in sarcoma patients during the COVID-19 pandemic. Patients with appointments during the first two months of the UK lockdown were invited to complete a survey. Questions included views on care modifications, COVID-19 worry and psychosocial impact, and EORTC-QLQ-C30 items. 350 patients completed the survey; median age 58 (16-92) years. Care modifications included telemedicine (74%) and postponement of appointments (34%), scans (34%) or treatment (10%). Most felt the quality of care was not affected (72%), however, social life (87%) and emotional wellbeing (41%) were affected. Worry about COVID-19 infection was moderately high (mean 5.8/10) and significantly related to higher cancer-related worry; associated with lower emotional functioning irrespective of treatment intent. Curative patients (44%) with low resilient coping scores had significantly higher COVID-19 worry. Patients who did not know their treatment intent (22%) had significantly higher COVID-19 worry and insomnia. In summary, care experiences were generally positive; however, cancer-related worry, low resilient coping and uncertainty about treatment intent were associated with COVID-19 worry. These patients may benefit from additional psychological support during the pandemic and beyond.

COVID-19 in cancer patients on systemic anti-cancer therapies: outcomes from the CAPITOL (COVID-19 Cancer PatIenT Outcomes in North London) cohort study.

BACKGROUND: Patients with cancer are hypothesised to be at increased risk of contracting COVID-19, leading to changes in treatment pathways in those treated with systemic anti-cancer treatments (SACT). This study investigated the outcomes of patients receiving SACT to assess whether they were at greater risk of contracting COVID-19 or having more severe outcomes. METHODS: Data was collected from all patients receiving SACT in two cancer centres as part of CAPITOL (COVID-19 Cancer PatIenT Outcomes in North London). The primary outcome was the effect of clinical characteristics on the incidence and severity of COVID-19 infection in patients on SACT. We used univariable and multivariable models to analyse outcomes, adjusting for age, gender and comorbidities. RESULTS: A total of 2871 patients receiving SACT from 2 March to 31 May 2020 were analysed; 68 (2.4%) were diagnosed with COVID-19. Cancer patients receiving SACT were more likely to die if they contracted COVID-19 than those who did not [adjusted (adj.) odds ratio (OR) 9.84; 95% confidence interval (CI) 5.73-16.9]. Receiving chemotherapy increased the risk of developing COVID-19 (adj. OR 2.99; 95% CI = 1.72-5.21), with high dose chemotherapy significantly increasing risk (adj. OR 2.36, 95% CI 1.35-6.48), as did the presence of comorbidities (adj. OR 2.29; 95% CI 1.19-4.38), and having a respiratory or intrathoracic neoplasm (adj. OR 2.12; 95% CI 1.04-4.36). Receiving targeted treatment had a protective effect (adj. OR 0.53; 95% CI 0.30-0.95). Treatment intent (curative versus palliative), hormonal- or immunotherapy and solid versus haematological cancers had no significant effect on risk. CONCLUSION: Patients on SACT are more likely to die if they contract COVID-19. Those on chemotherapy, particularly high dose chemotherapy, are more likely to contract COVID-19, while targeted treatment appears to be protective.

Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer.

Triple negative breast cancer (TNBC) encompasses molecularly different subgroups, with a subgroup harboring evidence of defective homologous recombination (HR) DNA repair. Here, within a phase 2 window clinical trial, RIO trial (EudraCT 2014-003319-12), we investigate the activity of PARP inhibitors in 43 patients with untreated TNBC. The primary end point, decreased Ki67, occured in 12% of TNBC. In secondary end point analyses, HR deficiency was identified in 69% of TNBC with the mutational-signature-based HRDetect assay. Cancers with HRDetect mutational signatures of HR deficiency had a functional defect in HR, assessed by impaired RAD51 foci formation on end of treatment biopsy. Following rucaparib treatment there was no association of Ki67 change with HR deficiency. In contrast, early circulating tumor DNA dynamics identified activity of rucaparib, with end of treatment ctDNA levels suppressed by rucaparib in mutation-signature HR-deficient cancers. In ad hoc analysis, rucaparib induced expression of interferon response genes in HR-deficient cancers. The majority of TNBCs have a defect in DNA repair, identifiable by mutational signature analysis, that may be targetable with PARP inhibitors.